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Normal and PPP-affected palmoplantar sweat gland express neuroendocrine markers chromogranins and synaptophysin differently
Abstract
Earlier findings indicate the acrosyringium as the target for the inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat gland apparatus seems to be an immune-competent structure that probably contributes to the defence of the skin. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ because it expresses cholineacetyl-transferase and acetylcholinesterase, nicotinic receptors, beta-adrenergic and angiotensin receptors. The aim of this study was to obtain further information about neuroendocrine properties of the sweat gland apparatus by examining the expression of common neuroendocrine markers synaptophysin and chromogranins A and B in healthy palmar skin and in PPP skin. Synaptophysin and chromogranins were expressed in the sweat glands and ducts with some variation in the pattern and intensity of the expression. In PPP skin the expression differed, being higher and lower, depending on the part of the sweat duct. Chromogranins were further expressed in the epidermis, endothelium and inflammatory cells, but its intensity was weaker in epidermis than in the sweat gland apparatus. In most cases, chromogranins in epidermis in involved PPP were weakly expressed compared to healthy controls. The presence of synaptophysin and chromogranins in palmoplantar skin may have marked neuroendocrine effects, and the palmoplantar skin is likely to have important neuroimmuno-endocrine properties. Moreover, the altered chromogranin expression in PPP skin might influence both the neuroendocrine and neuroimmunologic properties of palmoplantar skin in these patients. These results indicate important neuroendocrine properties of the palmoplantar skin.
... T lymphocytes predominate (CD3 + expression). 5,6 Contact dermatitis, pityriasis rubra pilaris, dyshidrotic eczema, and tinea should be taken into consideration in the differential diagnosis of PPP. ...
... Immunological processes in the course of PPP lead to accumulation of large numbers of granulocytes in the area of the sweat gland excretion tract, the acrosyringium. 5,13 Cytokines regulating immunological processes play a key role in the pathogenesis of the disorder. As in psoriasis, in PPP, increases in blood levels of pro-inflammatory interleukins such as tumor necrosis factor alpha (TNF-α), IL-17, IL-22, and interferon gamma (IFN-γ) are observed. ...
... Moreover, nicotine triggers macrophages and keratinocytes to release cytokines, and activates T lymphocytes, which sustains the chronic inflammatory process. 5,13 Recent studies indicate that acrosyringium plays a significant role in the development of PPP symptoms. The sweat glands are innervated by the cholinergic system, where acetylcholine (Ach) is the major inductor of sweating. ...
Palmoplantar pustulosis (PPP) is a chronic inflammatory disease, most often occurring in middle-aged women. In the course of the condition, painful skin lesions appear on the hands and feet, i.e., areas that are extremely important in everyday life. Therefore, the disease significantly reduces quality of life. The pathogenesis of this disease is poorly understood, although it is known that genetic, immunological and environmental factors play a role in its development. Clinical observations confirm the role of nicotine and contact allergens in the development of the lesions. The skin lesions can also occur as a side effect of certain medications. In some cases, PPP coexists with other diseases, i.e., seronegative arthropathies, as well as celiac and thyroid diseases. There is also a connection between the disease and infectious bacterial foci. Exacerbation of the skin lesions is triggered by stress. Therefore, patients require multidirectional tests, since finding the cause of the disease is essential to administering effective treatment.
... In addition, nicotine likewise affects the keratinocytes nearby the sweat glands and causes increased keratosis of the excretory ducts. 27,31 In fact, an association has been described between the cholinergic system and nicotine that appears to be based on the DovePress nicotine excretion in the eccrine ducts. Thus, nicotine seems to alter the expression of antigens in the acrosyringium, pulling Langerhans cells and provoke the production of IL-17 in the soles of the feet and palms. ...
... The immunological processes involved in PPP, lead to the accumulation, in the area of the the acrosyringium, of a substantial quantity of granulocytes. 27,31 The cytokines that regulate these processes play a fundamental role. As in psoriasis, in PPP, there is also an increase in the levels of proinflammatory interleukins in blood such as TNF-α, IL-22, IL-17 and gamma interferon (IFN-γ). ...
Palmoplantar pustulosis (PPP) is a rare, chronic, recurrent inflammatory disease that affects the palms and/or the soles with sterile, erupting pustules, which are debilitating and usually resistant to treatment. It has genetic, histopathologic and clinical features that are not present in psoriasis; thus, it can be classified as a variant of psoriasis or as a separate entity. Smoking and upper respiratory infections have been suggested as main triggers of PPP. PPP is a challenging disease to manage, and the treatment approach involves both topical and systemic therapies, as well as phototherapy and targeted molecules. No gold standard therapy has yet been identified, and none of the treatments are curative. In patients with mild disease, control may be achieved with on-demand occlusion of topical agents. In patients with moderate-to-severe PPP, phototherapy or a classical systemic agent (acitretin being the best treatment option, especially in combination with PUVA) may be effective. Refractory patients or those with contraindications to use these therapies may be good candidates for apremilast or biologic therapy, particularly anti-IL-17A and anti-IL-23 agents. Recent PPP trials are focusing on blockage of IL-36 or IL-1 pathways, which play an important role in innate immunity. Indeed, IL-36 isoforms have been strongly implicated in the pathogenesis of psoriasis. Therefore, blockage of the IL-36 pathway has become a new treatment target in PPP, and three studies are currently evaluating the use of monoclonal antibodies that block the IL-36 receptor in PPP: ANB019 and spesolimab (BI 655130). In this review, we explore the diagnosis, screening and treatment of patients with PPP.
... In addition, the present study showed intense synaptophysin immunofluorescent granules in sweat glands in the melatonin treated group. The presence of synaptophysin in the skin has pronounced neuroendocrine effects and neuroimmuno-endocrine properties 67 . That may attribute to a thermoregulatory effect of melatonin specifically in healthy males 67 . ...
... The presence of synaptophysin in the skin has pronounced neuroendocrine effects and neuroimmuno-endocrine properties 67 . That may attribute to a thermoregulatory effect of melatonin specifically in healthy males 67 . Melatonin also regulates hair pigmentation and growth 66 . ...
Fifteen adult Soay rams were employed in this study to investigate the effect of melatonin on the scrotal skin using histological, histochemical, and morphometrical analysis. The results revealed that the melatonin treated group showed a significant increase in the thickness of the epidermis, the cross-sectional area of blood capillaries and nerve fibers compared with the control one. In addition, obvious hypertrophy and hyperplasia were detected in the sebaceous glands in association with a significant increase in the number and diameter of apocrine sweat glands with well-developed secretory activity. S100 protein and cytokeratin-19 strongly stained the basal cells of sebaceous glands in the melatonin treated group incomparable to the control group. Moreover, the nerve fibers were intensively immunoreacted for S100 and cytokeratin proteins in the melatonin treated group in contrast to the control one. A high number of telocytes (TCs) could be identified in the treated group around the nerve fibers and blood vessels in the dermis. The number of Langerhans cells showed a significant increase in the melatonin groups that were identified by MHC II and PGP 9.5 within the epidermal layer. Furthermore, a significant increase in the number of dendritic cells was identified in the melatonin group, which were distributed within the dermis, around hair follicles, sebaceous glands, and sweat glands and were strongly expressed PGP-9.5, MHC-II, VAMP, SNAP, keratin-5, and cytokeratin-19 immunoreactivity. Notably, Merkel cells showed a significant increase in the number in the melatonin group that could be stained against nestin, SNAP, and VAMP. On the other hand, the secretory granules in sweat glands were exhibited a strong positive reactivity for synaptophysin in melatonin group. The current study showed that the administration of melatonin induced a stimulatory effect on keratinocytes, non-keratinocytes, sebaceous and sweat glands, hair follicles, as well as the vascular, neuronal, and cellular constituents of the dermis.
... Hagforsen et al. 1 proved that PPP patients showed a higher intensity of α-3-nAChR staining in the epidermis than healthy control. Additionally, cholinergic materials, such as nicotine, can cause keratinocytes to proliferate and release cytokines that sustain the chronic inflammatory process, suggesting the involvement of the eccrine glands in the pathogenesis of PPP [10][11][12][13] . ...
Background:
Palmoplantar pustulosis (PPP) is initiated from the acrosyringium. However, it is unclear whether PPP should be considered a distinct entity or should be classified into the spectrum of pustular psoriasis, also known as palmoplantar pustular psoriasis (PPPP).
Objective:
We evaluated the differences in immunohistochemical staining in patients with PPP to determine whether they can be classified into two groups based on psoriatic properties or acrosyringeal properties.
Methods:
Nineteen punch biopsy specimens diagnosed with PPP were collected. Antibodies were chosen for identifying the acrosyringeal properties of α-3-nicotine acetylcholine receptors (α-3-nAChR), psoriatic properties of interleukin (IL)-23 and IL-36R, inflammatory cell properties of human cathelicidin antimicrobial peptide 18/LL-37, IL-8, lipocalin-2 (LCN2), and CD3. The degree of staining of the epidermis was evaluated using the ordinal scale (0~3). The principal component analysis was used to derive principal components (PCs) of common variation between the stains, and the two groups were divided using PCs and cluster analysis.
Results:
Three main PCs explained 64% of the total variance in PPP. PC1 (pustular psoriasis properties) showed a higher correlation with IL-36R. PC2 (acrosyringeal/inflammatory properties) showed a higher correlation with α-3-nAChR, IL-8, LCN2, and CD3. PC3 (psoriasis properties) showed a higher correlation with IL-23. PC1 showed a statistically significant difference (p=0.0284) between the two groups. We identified three PCs associated with the pathomechanisms of PPP.
Conclusion:
Although PC1 showed a statistically significant difference between the two groups, we did not identify differential protein expression related to the pathogenesis between PPP and PPPP.
... 37 Acrosyringium in the palms/soles is reported to be the primary target for inflammation in PPP. 38,39 The sweat gland apparatus is a neuroendocrine organ expressing https://doi.org/10.2147/CPAA.S266223 ...
Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. PPP is refractory to various therapies such as topical ointment, oral medicine, and phototherapies. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP that severely impairs patients’ quality of life. Recently, guselkumab, a monoclonal antibody against IL-23, has been available for the treatment of PPP in Japan. The purpose of the present review is to describe the characteristics of Japanese PPP patients and biologic therapy of PPP/PAO using guselkumab. Most Japanese dermatologists consider PPP as a distinct entity and co-existence of PPP and psoriasis is rare. However, outside Japan, PPP is often considered to be palmoplantar psoriasis, and extra-palmoplantar lesions associated with PPP are regarded as psoriasis. PPP develops or exacerbates either with or without arthralgia, following focal infections, such as tonsillitis, odontogenic infection, and sinusitis. Treatment of focal infection results in dramatic effects on cutaneous lesions as well as joint pain. By contrast, we sometimes see patients whose skin/joint symptoms do not improve after treatment of focal infection, whose focus of infection cannot be identified even in a detailed examination, and/or who refuse tonsillectomy even if strongly recommended. Such cases are considered to be indications of biologics. In this review, clinical features, pathophysiology and guselkumab therapy are discussed.
... The increased expression of alpha7 nAChR which controls homeostasis and terminal differentiation of epidermal cells was observed on the sweat glands and in the epidermis of patients with PPP compared to healthy individuals. [22][23][24] These receptors show greater affinity for nicotine than for acetylcholine. New theory explains that nicotine-stimulated nAChR play a role in the PPP pathogenesis by leading to the accumulation of neutrophils and eosinophils in the epidermis. ...
Background:
Palmoplantar pustulosis (PPP) is a chronic inflammatory disease with poorly understood pathogenesis. The disease has a chronic course with improvements and exacerbations. Due to palmoplantar location, PPP has a severely negative impact on patients' quality of life.
Objectives:
To identify demographic and environmental factors, concomitant diseases, medications, and bacterial factors which may affect the course of PPP.
Material and methods:
A total of 51 patients suffering from PPP took part in the study. They were classified according to the Palmoplantar Pustulosis Psoriasis Area and Severity Index (ppPASI) into 3 groups due to the severity of the disease. Pack-year of smoking score was established as a quotient of packets smoked every 24 h and the years of being addicted. Diagnosis of metabolic syndrome was based on the IDF criteria from 2009. Chlamydia trachomatis was detected using enzyme-linked immunosorbent assay (ELISA) technique, Staphylococcus aureus by the culture swabs. Contact hypersensitivity was examined with the T.R.U.E. test.
Results:
Significantly high severity of PPP was observed in patients addicted to smoking with a high pack-year score (p = 0.03). Significantly lower intensity of PPP lesions was observed in patients treated with ibuprofen (p < 0.01). There was no correlation between severity of PPP skin lesions and comorbidities.
Conclusions:
Addiction to cigarette smoking and a high pack-year score aggravates the course of PPP. Treatment with ibuprofen can improve the course of the disease.
... In chronic PPI therapy (over 1 year), it may take up to 8 weeks for CgA levels to normalize (12). Interestingly, CgA expression has also been identified in sweat glands and ducts and in particular on the palmoplantar skin, but its functional role has not been elucidated (13). Considering that CgA is present in sweat glands and is a precursor to several bioactive peptides, we postulated that elevations in CgA levels may play a role in PPI-induced hyperhidrosis. ...
Objective: To discuss the prevalence of hyperhidrosis, its association with proton pump inhibitor (PPI) use, and possible underlying mechanism(s) accounting for PPI-induced hyperhidrosis.
Methods: We describe 2 patients who presented with hyperhidrosis while on PPI therapy, review the literature regarding PPI-associated hyperhidrosis, discuss a potential mechanism, and provide recommendations for hyperhidrosis evaluation in the setting of PPI use.
Results: A 62-year-old man (case 1) presented with hyperhidrosis. Biochemical workup was nondiagnostic except for elevated chromogranin A (CgA) levels. He had been taking lansoprazole. Since PPI therapy can increase CgA levels, lansoprazole was discontinued. CgA levels decreased by 2 weeks, and hyperhidrosis resolved within 4 weeks. Symptoms recurred once PPI therapy was restarted. An 83-year-old man (case 2) presented with hyperhidrosis. He had been on omeprazole for 9 months. Omeprazole was held before performing extensive biochemical workup. Hyperhidrosis resolved after 5 days and recurred within 3 days of re-introducing omeprazole. Omeprazole was switched to ranitidine, and hyperhidrosis resolved within 1 month.
Conclusion: PPI-induced hyperhidrosis is an uncommon side effect, and a mechanism has not been described. CgA is a precursor of several bioactive peptides, and levels increase while on PPIs. Expression of CgA has been identified on sweat glands and ducts. Elevated CgA levels may play a functional role in PPI-induced hyperhidrosis, but this remains to be demonstrated. In the absence of an apparent cause of hyperhidrosis in a patient on PPI therapy, a trial off PPI should be considered prior to embarking on costly and extensive workup.
Abbreviations: CgA = chromogranin A; ECL = enterochromaffin-like; GERD = gastroesophageal reflux disease; PPI = proton pump inhibitor
Background
Smoking is a known risk factor for psoriasis; however, the impact of smoking cessation on psoriasis has seldom been evaluated.
Objectives
We aimed to examine the effects of smoking cessation on the development of psoriasis vulgaris (PsV), palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP).
Methods
Using the Korean National Health Insurance Service database, we retrospectively compiled a cohort of 5,784,973 participants without psoriasis, analysed their changes in smoking status from 2004 to 2007 and followed up new cases of psoriasis until 2021. The psoriasis risks were compared with those of sustained smokers, smoking quitters, sustained ex-smokers, and never smokers using multivariate Cox proportional hazards models.
Results
The mean age of the participants was 47.1 years (standard deviation, 13.5), and 3,092,426 (53.5%) were male. During 77,990,688 person-years, 67,364 psoriasis cases were identified. Compared with sustained smokers, smoking quitters showed a reduced risk of developing psoriasis (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.87–0.95), specifically PsV (aHR 0.92; 95% CI 0.88–0.97) and PPP (aHR 0.71; 95% CI 0.63–0.79). The reduction in risk due to smoking cessation was more prominent in sustained ex-smokers (psoriasis: aHR 0.77, 95% CI 0.74–0.79; PsV: aHR 0.76, 95% CI 0.73–0.79; PPP: aHR 0.56, 95% CI 0.51–0.61; GPP: aHR 0.64; 95% CI 0.52–0.78). When conducting sensitivity analyses to address the potential for changes in smoking habits after 2007, the results and trends were consistent with the main findings, and a more pronounced significance was observed.
Conclusions
Compared with continuous smoking, smoking cessation was associated with a decreased risk of developing psoriasis. The risk-reducing effect of smoking cessation was more pronounced in those maintaining a smoke-free status. Smoking cessation and the maintenance of a smoke-free status should be encouraged to prevent the development of psoriasis and all other smoking-related diseases.
Pustulotic arthro‐osteitis (PAO) has been studied primarily in Japan. However, there is a lack of research regarding its clinical features among large populations in other countries and it is often believed to be similar to psoriatic arthritis (PsA). Although the association between psoriasis (PsO) and palmoplantar pustulosis (PPP) is debatable, differences in the clinical characteristics between PsA and PAO might support the notion that PsO and PPP are distinct entities. This study aimed to investigate the clinical characteristics of PAO in Korean patients and to compare them with those of PsA. We retrospectively reviewed the medical records of patients diagnosed with PPP, PAO, and PsA. Among 266 patients with PPP, 13.2% had PAO. Unlike Japanese patients with PAO, Korean patients had a relatively lower involvement of the chest wall. PAO patients demonstrated lower age of onset, higher proportion of females, and higher severity of cutaneous eruptions compared to PPP patients without PAO, but the differences were not statistically significant. Female predominance was prominent in PAO compared to PsA. Cutaneous eruptions occurred earlier than joint symptoms in 83.5% of the patients with PsA and in 42.9% of the patients with PAO. PAO involved axial joints more frequently compared to PsA, especially the chest wall and spine. PsA mainly involved the peripheral joints, especially the metacarpophalangeal joints and distal interphalangeal joints of the hands and feet. In conclusion, PAO and PsA exhibited different demographics and locations of joint involvement, supporting the notion that PPP and PsO are separate disorders. Many PAO patients presented with joint symptoms before the appearance of skin eruptions, underlining the important role of dermatologists in recognizing PAO among PPP patients. Physicians should be aware of the characteristics of PAO while treating patients with PPP.
Palmoplantar pustulosis is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. Palmoplantar pustulosis has many similar aspects to psoriasis, either plaque and pustular type, namely familial occurrence between palmoplantar pustulosis and psoriasis, the appearance of the Köbner phenomenon, joint involvement, and nail involvement. Pustular psoriasis is classified into generalized and localized types, and there are a number of papers regarding palmoplantar pustulosis as an acral variant of localized pustular psoriasis. Many Japanese dermatologists consider palmoplantar pustulosis to be a distinct entity from pustular psoriasis, and the coexistence of palmoplantar pustulosis and psoriasis is rare. However, outside Japan, palmoplantar pustulosis is often considered to be palmoplantar psoriasis or palmoplantar pustular psoriasis, and extra-palmoplantar lesions are also considered to be psoriasis. The purpose of the current review is to compare the similarities and differences between palmoplantar pustulosis and generalized/localized pustular psoriasis. Japanese patients with palmoplantar pustulosis have a close relationship with focal infection, and the associated bone-joint manifestation exclusively involves the anterior chest wall. Furthermore, pediatric occurrence of palmoplantar pustulosis is extremely rare, and difference of genetic background between palmoplantar pustulosis and psoriasis has also been reported. Treatment of focal infection often results in dramatic effects on both cutaneous lesions and joint pain of palmoplantar pustulosis. Those findings suggest that palmoplantar pustulosis should be separately considered from either palmoplantar psoriasis or palmoplantar pustular psoriasis. The clinicopathological features and therapeutic approach of both diseases are discussed.
For patients with extensive skin defects, loss of sweat glands (SwGs) greatly decreases their quality of life. Indeed, difficulties in thermoregulation, ion reabsorption, and maintaining fluid balance might render them susceptible to hyperthermia, heatstroke, or even death. Despite extensive studies on the stem cell biology of the skin in recent years, in-situ regeneration of SwGs with both structural and functional fidelity is still challenging because of the limited regenerative capacity and cell fate control of resident progenitors. To overcome these challenges, one must consider both the intrinsic factors relevant to genetic and epigenetic regulation and cues from the cellular microenvironment. Here, we describe recent progress in molecular biology, developmental pathways, and cellular evolution associated with SwG development and maturation. This is followed by a summary of the current strategies used for cell-fate modulation, transmembrane drug delivery, and scaffold design associated with SwG regeneration. Finally, we offer perspectives for creating more sophisticated systems to accelerate patients’ innate healing capacity and developing engineered skin constructs to treat or replace damaged tissues structurally and functionally.
Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles. The purpose of this review was to describe the characteristics of Japanese PPP patients as PPP is frequently observed within the Japanese population. Most Japanese dermatologists consider PPP a distinct entity, and co-existence of PPP and psoriasis is rare; however, outside Japan, PPP is often considered to be palmoplantar psoriasis, and an extra-palmoplantar lesion associated with PPP is considered to be psoriasis. PPP frequently develops or exacerbates following focal infections such as tonsillitis, odontogenic infection, and sinusitis, either with or without arthralgia. Pustulotic arthro-osteitis (PAO) is a major comorbidity of PPP, most often affecting the anterior chest wall. In Japanese patients, PAO is frequently seen, whereas cases of SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome with symptoms other than PPP and sternocostoclavicular joint pain are extremely rare. A difference in incidence depending on race suggests that different genetic backgrounds may be responsible for susceptibility to these disorders. The treatment of focal infections often results in dramatic effects on cutaneous lesions, as well as joint pain. The characteristics of Japanese patients with PPP are female predominance, mostly smokers, rare co-existence with psoriasis, frequent association with PAO, almost no accompanying celiac disease, and closely associated with focal infection. PPP should be separately considered from palmoplantar psoriasis.
Palmoplantar pustulosis (PPP) is a chronic inflammatory disorder characterized by sterile pustules predominantly involving the palms and soles of middle-aged women. PPP frequently develops or exacerbates following focal infections, such as tonsillitis, odontogenic infection and sinusitis, either with or without arthralgia and/or extra-palmoplantar lesions. Pustulotic arthro-osteitis (PAO) is a joint comorbidity of PPP, most often affecting the anterior chest wall. PAO is sometimes regarded as the same entity as synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome, and may be a subtype or incomplete type of SAPHO syndrome; however, there are several differences. In Japanese patients, PPP with PAO is frequently seen, whereas SAPHO syndrome in the true meaning is rare. A difference of incidence depending on race suggests that different genetic backgrounds may be responsible for susceptibility to these disorders. Bacterial infection, especially Propionibacterium acnes, is suggested to play an important role in the pathogenesis of SAPHO syndrome. P. acnes is responsible for acne, however, bacterium is unassociated with PPP skin lesions which are characterized by sterile pustules. On the other hand, PAO is frequently triggered by focal infection, and treatment of focal infection results in dramatic effects on the release of joint pain. This paper reviews current insights into the clinicopathophysiology of PAO, and discusses its possible mechanisms in comparison with SAPHO syndrome.
Palmoplantar pustulosis (PPP) is difficult to treat. There is little hard evidence for the efficacy of any treatment and no published guidelines for its management. A number of exacerbating factors are well documented and there is some evidence for the importance of others. Smoking is the most recognized environmental trigger and recent research has concentrated on the role of eccrine sweat glands in this regard. Other factors, including tonsillar streptococcal infection and gluten sensitivity, may be important in selected cases. The aim of this review is to challenge dermatologists to consider alternative management strategies for PPP and design clinical trials that will enable the development of useful therapeutic guidelines.
The barrier function of the skin may be characterized by a number of biophysical and molecular methods. Variation in the barrier properties as a function of depth has not been explored in detail.
To characterize changes in corneocyte surface area, corneocyte maturity, selected protease activities and transepidermal water loss (TEWL) in the ventral forearm with increasing depth.
The left mid-ventral forearm of 22 healthy volunteers was selected as the study site. After tape stripping, corneocyte maturity and surface area were assessed. The protease activity of the desquamatory kallikrein proteases, KLK5 and KLK7, and inflammatory tryptase was measured using a fluorogenic probe assay. Protein content and TEWL were also recorded.
Corneocyte maturity and surface area decreased with increasing number of tape strippings, i.e. depth into the skin. More mature corneocytes were typically larger than less mature corneocytes. The protease activities of both the desquamatory and inflammatory enzymes together with the protein content were highest in the outer layers of the stratum corneum and decreased with depth. As expected, TEWL increased as more stratum corneum layers were removed. There were no statistical differences between men and women or caucasian and black subjects for all of the parameters studied.
The techniques used in this study provide rapid noninvasive measures of the spatial distribution of corneocyte maturity and surface area as well as protease activity and protein content within different levels of the stratum corneum layers. The methods used will allow mechanistic insight into the effects of formulation excipients and active ingredients on epidermal turnover and skin barrier function.
Recently, we have isolated from bovine chromaffin granules and identified two natural peptides possessing antibacterial activity:
secretolytin (chromogranin B 614-626) and enkelytin (proenkephalin-A 209-237). Here, we characterize a large natural fragment,
corresponding to chromogranin A 79-431, that inhibits growth of both Gram-positive and Gram-negative bacteria. The aim of
the present work was to determine the shortest active peptide located in the 79-431 chromogranin A region. Three peptides,
which shared the same 173-194 chromogranin A sequence (YPGPQAKEDSEGPSQGPASREK) but differed in post-translational modifications,
including O-glycosylation and tyrosine phosphorylation, were isolated. A detailed study using microsequencing and mass spectrometry allowed
us to correlate their antibacterial activity with these post-translational modifications. The chromogranin A precursor fragment
(79-431) and the active glycosylated and phosphorylated peptides were, respectively, named prochromacin and chromacin (P,
G, and PG for phosphorylated, glycosylated, and phosphorylated-glycosylated form).
Catecholamine secretory vesicle core proteins (chromogranins) contain an activity that inhibits catecholamine release, but the identity of the responsible peptide has been elusive. Size-fractionated chromogranins antagonized nicotinic cholinergic-stimulated catecholamine secretion; the inhibitor was enriched in processed chromogranin fragments, and was liberated from purified chromogranin A. Of 15 synthetic peptides spanning approximately 80% of chromogranin A, one (bovine chromogranin A344-364 [RSMRLSFRARGYGFRGPGLQL], or catestatin) was a potent, dose-dependent (IC50 approximately 200 nM), reversible secretory inhibitor on pheochromocytoma and adrenal chromaffin cells, as well as noradrenergic neurites. An antibody directed against this peptide blocked the inhibitory effect of chromogranin A proteolytic fragments on nicotinic-stimulated catecholamine secretion. This region of chromogranin A is extensively processed within chromaffin vesicles in vivo. The inhibitory effect was specific for nicotinic cholinergic stimulation of catecholamine release, and was shared by this chromogranin A region from several species. Nicotinic cationic (Na+, Ca2+) signal transduction was specifically disrupted by catestatin. Even high-dose nicotine failed to overcome the inhibition, suggesting noncompetitive nicotinic antagonism. This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.
We studied the immunoreactivity of 12 different region-specific antibodies to the chromogranin A (CgA) molecule in the four major neuroendocrine cell types of the human pancreas by using double immunofluorescence techniques. The antibodies raised to the N-terminal and midportions of CgA showed, on the whole, stronger immunoreactivity than did the C-terminal antibodies, with a few exceptions. Often the immunoreactivity was stronger in glucagon cells. Insulin cells expressed immunoreactivity to all region-specific antibodies, but glucagon cells were nonreactive to two antibodies. Somatostatin cells reacted only with the C-terminal antibodies (amino acid sequences CgA 411-424), while PP cells were stained with four CgA region-specific antibodies between amino acid sequences 63-195. The cause of these differences may be that the CgA molecule is cleaved, partly masked, or partly translated from CgA mRNA. Microwave treatment improved only the staining with the CgA 361-372 antibodies, which indicates that masking is not the sole or entire cause. Our findings may indicate that the CgA molecule is cleaved in different ways in the various pancreatic endocrine cell types, giving rise to a variety of biologically functional fragments.
Antimicrobial peptides are an important component of the innate response in many species. Here we describe the isolation of the gene Dermcidin, which encodes an antimicrobial peptide that has a broad spectrum of activity and no homology to other known antimicrobial peptides. This protein was specifically and constitutively expressed in the sweat glands, secreted into the sweat and transported to the epidermal surface. In sweat, a proteolytically processed 47-amino acid peptide was generated that showed antimicrobial activity in response to a variety of pathogenic microorganisms. The activity of the peptide was maintained over a broad pH range and in high salt concentrations that resembled the conditions in human sweat. This indicated that sweat plays a role in the regulation of human skin flora through the presence of an antimicrobial peptide. This peptide may help limit infection by potential pathogens in the first few hours following bacterial colonization.
Chromogranin (Cg) B is an acidic glycoprotein present in neuroendocrine tissue. The sequence shows several dibasic amino acid positions susceptible to proteolytic cleavage. The purpose of this study was to elucidate the expression of CgB epitopes in the human endocrine pancreas. Tissue sections of six human pancreata were immunostained with 16 different region-specific antibodies to the CgB molecule, using double immunofluorescence techniques. The CgB epitope pattern varied in the four major islet cell types. B (insulin)-cells expressed immunoreactivity to all region-specific antibodies. The antibodies to the N-terminal and mid-portions of CgB showed moderate immunoreactivity, the C-terminal antibodies weak. A (glucagon)-cells were reactive only to the N-terminal and mid-portion antibodies but, after microwave pretreatment, to all antibodies, whereas D (somatostatin)-cells expressed only the sequence CgB 244-255 and a subpopulation CgB 580-595. PP (pancreatic polypeptide) cells were immunostained with antibodies between CgB 1-417 and a few with CgB 580-593. The fragment CgB 244-255 was expressed in all four cell types. The cause of these differences may be cell-specific cleavage or masking of the molecule, but varying translation of CgB mRNA is also possible. The extent to which these epitopes reflect fragments having biological functions remains to be evaluated.
We studied the immunoreactivity of 12 different region-specific antibodies to the chromogranin A (CgA) molecule in the various neuroendocrine cell types of the human gastrointestinal (GI) tract by using double immunofluorescence techniques. These staining results were compared with others obtained with a commercial monoclonal CgA antibody (LK2H10). G (gastrin)-cells showed immunoreactivity to virtually all region-specific antibodies, but with varying frequency. Most intestinal EC (enterochromaffin)- and L (enteroglucagon)-cells were immunoreactive to the antibodies to the N-terminal and mid-portion of the CgA molecule, whereas the EC-cells in the stomach reacted with fewer region-specific antibodies. D (somatostatin)-cells reacted to the CgA 411-424 antibody and only occasionally showed immunoreactivity to the other CgA antibodies. A larger cytoplasmic area was stained with the antibodies to CgA 17-38 and 176-195 than with the other antibodies tested. These differences in staining pattern may reflect different cleavage of the CgA molecule in different cell types and at different regions of the GI tract.
Palmoplantar pustulosis is characterized by pustule formation in the acrosyringium. Nearly 50% of palmoplantar pustulosis sera produce immunofluorescence of the palmar papillary endothelium from healthy subjects, but also of the endothelium of normal parathyroid gland. With a case-control design the levels of calcium and parathyroid hormone in serum were measured in 60 women with palmoplantar pustulosis and 154 randomly selected population-based control women. One-third of the controls had been smokers, whereas 95% of the cases were or had been smokers. Mean age-adjusted serum calcium was increased in the patients compared with the controls (2.43 vs 2.36 mmol/l; p<0.0001), whereas the parathyroid hormone concentration was suppressed (23.2 vs 31.1 ng/l; p<0.0001). The plasma levels of parathyroid hormone-related protein were normal in patients but there was a strong expression of this protein in the acrosyringium both in palmoplantar pustulosis and control skin. As even a marginal elevation of serum calcium is associated with an increased risk for diabetes, cardiovascular disease and psychiatric disease, we analysed the risk for these disorders in palmoplantar pustulosis patients compared with that in the control group. Both diabetes mellitus and psychiatric disorders were associated with palmoplantar pustulosis with an odds ratio of 8.7 (95% CI 3.3-22.8) and 5.6 (95% CI 2.2-14.4), respectively. Palmoplantar pustulosis is a complex disease with an increased risk for several non-dermatological disorders. The role of the mildly increased serum calcium for the high risk for diabetes and depression deserves to be studied.
This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.
Epithelia establish a microbial barrier against infection through the production of antimicrobial peptides (AMPs). In this study, we investigated whether catestatin (Cst), a peptide derived from the neuroendocrine protein chromogranin A (CHGA), is a functional AMP and is present in the epidermis. We show that Cst is antimicrobial against relevant skin microbes, including Gram-positive and Gram-negative bacteria, yeast, and fungi. The antimicrobial mechanism of Cst was found to be similar to other AMPs, as it was dependent on bacterial charge and growth conditions, and induced membrane disruption. The potential relevance of Cst against skin pathogens was supported by the observation that CHGA was expressed in keratinocytes. In human skin, CHGA was found to be proteolytically processed into the antimicrobial fragment Cst, thus enabling its AMP function. Furthermore, Cst expression in murine skin increased in response to injury and infection, providing potential for increased protection against infection. These data demonstrate that a neuroendocrine peptide has antimicrobial function against a wide assortment of skin pathogens and is upregulated upon injury, thus demonstrating a direct link between the neuroendocrine and cutaneous immune systems.
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Polyclonal antibodies directed towards synaptophysin were raised against a synthesised peptide corresponding to amino acids 246 to 260 of the human synaptophysin sequence. The antibodies, when applied for immunocytochemical staining, showed a staining pattern identical to that of the commercially available monoclonal antibody SY-38. A radioimmunoassay for measurements of synaptophysin was developed using these antibodies and the peptide as standard and tracer. The radioimmunoassay was used for optimising the conditions for purification of synaptophysin from rat brain. No synaptophysin was detected in blood plasma in humans, not even during an embolisation treatment of tumour metastases in the liver, which induced tumour cell necrosis, in a patient with carcinoid tumours. By radioimmunoassay, synaptophysin was detected in cell homogenate from the PC-12 (160 ng/mg) and LCC-18 (40 ng/mg) cell lines and in the cell culture media. In the LCC-18 cell line the synaptophysin immunoreactivity was found in the plasma membrane, and the presence of synaptophysin was confirmed both by radioimmunoassay measurements and by the Northern blot technique. These data indicate that measurements of synaptophysin using this radioimmunoassay are reliable and that the assay can serve as a useful tool in further explorations of the biological effects of synaptophysin.
The chromogranins A (CgA) and B (CgB) and secretogranin II (SgII) constitute the main members of a family of uniquely acidic secretory proteins in elements of the diffuse neuroendocrine system. These genetically distinct proteins, CgA, CgB, SgII and the less well known secretogranins III-VII are collectively referred to as 'granins' and characterised by numerous pairs of basic amino acids as potential cleavage sites for processing by the co-stored prohormone converting enzymes PC 1/3 and PC2. This review is directed towards comparative and functional aspects of the granins with emphasis on their phylogenetically conserved sequences. Recent developments provide ample evidence of widely different effects and targets for the intact granins and their derived peptides, intracellularly in the directed trafficking of storage components during granule maturation and extracellularly in autocrine, paracrine and endocrine interactions. Most of the effects assigned to the granin derived peptides fit into patterns of direct or indirect inhibitory modulations of major functions. So far, peptides derived from CgA (vasostatins, chromacin, pancreastatin, WE-14, catestatin and parastatin), CgB (secretolytin) and SgII (secretoneurin) are the most likely candidates for granin-derived regulatory peptides, of postulated relevance not only for homeostatic processes, but also for tissue assembly and repair, inflammatory responses and the first line of defence against invading microorganisms.
Bouin-fixed paraffin sections or acetone-fixed cryostat sections were labelled with the avidinbiotin complex (ABC) or peroxidase-antiperoxidase (PAP) method using three monoclonal antibodies (MAbs) and two polyclonal antisera to human recombinant interleukin i beta (IL-iβ) and three polyclonal antisera to human recombinant interleukin iα (IL-iα). In the secretory coil both IL-α and β were detected in the clear, but not in the dark cells. Both luminal and basal cells of the coiled and straight ducts expressed IL-iα and β, the IL-i labelling being more intense in the luminal cells. IL-i was not usually detected in the initial portion of the intraepidermal eccrine sweat duct, whereas intense labelling was seen in the upper part including through the stratum corneum. In skin biopsies of the palm, taken after exercise, there was only faint IL-i labelling of the secretory cells, whereas the luminal cells of the dermal ducts showed intense labelling for both IL-iα and β. In the acrosyringium, exercise did not alter the pattern for IL-iα and β, except that in the palm, some of the antibodies to IL-iβ produced a more intense immunolabelling of the acrosyringeal cells. This study identifies a distinct and similar distribution of the two forms of IL-i throughout the eccrine sweat-gland apparatus and indicates that part of the IL-i epidermal pool originates from the sweat.
Palmoplantar pustulosis (PPP) is a chronic and intensely inflammatory skin disease with pustules, erythema and scaling localized to the palms and soles. To date, no specific treatment is known. Earlier findings indicate the acrosyringium as the target for the inflammation.
To identify specific features of the PPP inflammatory cell infiltrate and mediators of inflammation, which might provide insight into the pathogenesis and possible future treatment of the disease.
Skin biopsies were taken from 23 patients with typical PPP (23 from involved skin and seven from noninvolved skin) and from 18 healthy controls (10 nonsmokers, eight smokers). Cell infiltrates and inflammation mediators were studied with immunohistochemistry.
A strong inflammation was observed in lesional skin of PPP. Our main findings of Langerhans cells and interleukin-17 close to or in the acrosyringium differs from findings in psoriasis vulgaris. Other inflammatory cells such as CD4+, CD8+, regulatory T cells and CD11a+ cells were also accumulated close to the sweat duct in epidermis and papillary dermis. More CD4+, CD8+, Langerhans cells, plasmacytoid dendritic cells and a higher proportion of regulatory T cells/CD3+ cells were seen in noninvolved palmar skin from patients with PPP compared with healthy controls.
Our novel findings indicate that the inflammation in PPP is initiated by the 'stand-by' innate immune system at the acrosyringium.
Summary The demonstration of HLA-DR on human acrosyringium has led to the suggestion that eccrine epithelium, through its interaction with certain molecules, might play an active role in epidermal immune responses. An immunohistochemical study was undertaken to identify the antigenic profile of acrosyringium in normal skin and following the intradermal administration of a T-lymphocyte-derived cytokine, interferon gamma (TFN-γ). Acrosyringium in normal skin, in contrast to interappendageal epidermis, was found to lack CDla+ Langerhans cells. However, antigens CD36 (OKM5) and Ll (MAC387) were uniquely expressed by keratinocytes immediately adjacent to the distal portion of acrosyringium. Constitutive expression of each class II MHC antigen, namely HLA-DR, DP and DQ was observed on luminal acrosyringial cells. EBMl 1 antigen (CD68), a mononucler cell determinant, was similarly expressed on acrosyringial epithelium in normal skin. Following intradermal administration of IFN-γ. Intercellular adhesion molecule-1 (ICAM-I) (CD54) was induced on acrosyringial epithelium and the expression of HLA-DR was intensified. A range of other markers including CD3, CD4, CD8, CDl la, CDl l b and CDl5 were not expressed by acrosyringium either in normal skin or after administration of IFN-γ.
Expression of antigens associated with cell-mediated immune mechanisms on acrosyringium is consistent with the hypothesis that it may have an immunological role in epidermal immune responses.
The development of chromaffin and neuronal features in the adrenal medulla was studied in normal human fetuses with gestational ages (GAs) of 6-34 weeks. Monoclonal antibodies specific for chromogranin A, synaptophysin, and tyrosine hydroxylase; for different subunits and phosphoisoforms of neurofilament (NF) proteins; and for microtubule-associated proteins were applied. Morphologically, two major cell types could be distinguished, i.e., "large" cells with pale nuclei and ill-defined cytoplasm, which were present from 9 weeks GA on, and clusters of "small," primitive appearing cells, present from 14 weeks GA on. The large cells were immunoreactive for chromogranin A, synaptophysin, tyrosine hydroxylase, and NF proteins, similar to adult chromaffin cells. In contrast, small cells expressed NF proteins and tyrosine hydroxylase, but not chromogranin A or synaptophysin, more resembling ganglion cells in the adult adrenal medulla. At the latest developmental stages large cells were observed in the center of the clusters of "small" cells, which morphologically resembled immature ganglion cells and expressed NF proteins in their perikarya. These observations indicate that chromaffin and ganglion cells establish their immunophenotype early in embryogenesis. They suggest that "large" and "small" cells are progenitors of the chromaffin and the ganglion cells, respectively, of the mature adrenal medulla.
Chromogranin A (CGA) is a ubiquitous 48-kDa secretory protein present in adrenal medulla, anterior pituitary, central and peripheral nervous system, endocrine gut, thyroid, parathyroid, and endocrine pancreas. Recently, we have demonstrated that the protein could be a precursor of bioactive peptides capable of modulating catecholamine secretion from cultured adrenal medullary chromaffin cells. Here we cleaved CGA purified from bovine chromaffin granules with endoproteinase Lys-C, and we isolated and partially sequenced the peptide inhibiting catecholamine secretion from cultured chromaffin cells. A corresponding synthetic peptide composed of the first 20 N-terminal amino acids produced a dose-dependent inhibition in the 10(-9) to 10(-6) M range (with an ID50 of 5 nM) of the catecholamine secretion evoked by carbamoylcholine or by potassium at a depolarizing concentration. This peptide affected secretagogue-induced calcium fluxes but did not alter sodium fluxes. It was found to increase desensitization of cell responses and to modify the kinetics of catecholamine release. Our results indicate that the peptide is extracellularly generated from CGA by a calcium-dependent proteolytic mechanism. We suggest that this peptide, named chromostatin, may be an endocrine modulator of catecholamine-associated responses.
Chromogranin-A (CGA), which accounts for more than half the soluble matrix protein in secretory granules of various neuroendocrine cells, has a wide spectrum of potential biological roles and is considered an important marker of the diffuse neuroendocrine system (DNES). Light and electron microscopic immunohistochemistry of mammalian skin revealed that Merkel cells are exclusively CGA-immunoreactive (ir) and that the immunoreaction is localized in the secretory granules. This finding supports the classification of the Merkel cell as a member of the DNES. The CGA immunoreactivity was restricted to Merkel cells of pigs and humans. In human embryonic skin, CGA was expressed in Merkel cells as early as week 11 of gestation. The antisera differed in their ability to stain Merkel cells in different species and developmental stages, reflecting a variable chemical coding for CGA. CGA probably represents a precursor for smaller regulatory peptides or acts as a messenger on its own on various target tissues, suggesting a neurosecretory function of the Merkel cell.
Synaptophysin is an integral membrane glycoprotein (Mr 38,000) that occurs in presynaptic vesicles of neurons and in similar vesicles of the adrenal medulla. By using a monoclonal antibody to this protein (SY38), we have found, by immunohistochemistry and immunoblotting, that an identical or similar protein is also expressed in neuroendocrine tumors of neural type, such as pheochromocytomas and paragangliomas. In addition, this protein occurs in certain neuroendocrine epithelial cells, such as pancreatic islet cells; in a variety of neuroendocrine epithelial tumors, including isletcell adenomas and carcinomas and several carcinoids and neuroendocrine carcinomas of the gastrointestinal and the bronchial tracts; and in medullary carcinomas of the thyroid. Our results show that synaptophysin, and the vesicles that contain it, can occur in normal and neoplastic neuroendocrine cells of neural type, as demonstrated by colocalization with neurofilaments, as well as in those of epithelial type, as shown by colocalization with cytokeratin filaments and desmoplakins. We conclude that synaptophysin is expressed independently of other neuronal differentiation markers and propose that it be used as a differentiation marker in tumor diagnosis.
Antibodies to chromogranin, a secretory protein marker for the diffuse neuroendocrine system, were used to analyze rat lymphoreticular tissues by means of immunochemistry and immunohistochemistry. Chromogranin-positive cells were present in spleen, lymph node, thymus, and fetal liver. When these organs were gently dispersed and separated on a Ficoll gradient, the chromogranin-immunoreactive cells became enriched in the dense red-cell pellets. The unexpected distribution of these neuroendocrine cells in all immunologically relevant structures suggests that they may link the nervous and immunological systems.
Polyclonal antibodies directed towards synaptophysin were raised against a synthesised peptide corresponding to amino acids 246 to 260 of the human synaptophysin sequence. The antibodies, when applied for immunocytochemical staining, showed a staining pattern identical to that of the commercially available monoclonal antibody SY-38. A radioimmunoassay for measurements of synaptophysin was developed using these antibodies and the peptide as standard and tracer. The radioimmunoassay was used for optimising the conditions for purification of synaptophysin from rat brain. No synaptophysin was detected in blood plasma in humans, not even during an embolisation treatment of tumour metastases in the liver, which induced tumour cell necrosis, in a patient with carcinoid tumours. By radioimmunoassay, synaptophysin was detected in cell homogenate from the PC-12 (160 ng/mg) and LCC-18 (40 ng/mg) cell lines and in the cell culture media. In the LCC-18 cell line the synaptophysin immunoreactivity was found in the plasma membrane, and the presence of synaptophysin was confirmed both by radioimmunoassay measurements and by the Northern blot technique. These data indicate that measurements of synaptophysin using this radioimmunoassay are reliable and that the assay can serve as a useful tool in further explorations of the biological effects of synaptophysin.
The parathyroid gland responds to decreases in levels of extracellular calcium by increasing the secretion of both PTH and chromogranin-A (CGA) in approximately equal molar ratios. Because CGA has been suggested to be a precursor for biologically active peptides, we used primary cultures of bovine parathyroid cells to examine the effects of various peptides from CGA as well as analogous peptides from chromogranin-B (CGB) on PTH secretion. In concentrations from 10(-8)-10(-7) M, amino-terminal peptide CGA-(1-76) effectively inhibited the release of PTH in response to low extracellular calcium. Truncated analogs of this peptide, CGA-(1-40), CGB-(1-41), and CGA-(17-38) were also found to be active in the following order: CGA-(1-76) = CGA-(1-40) = CGB-(1-41) > CGA-(17-38). The biological activity of CGA-(1-40) was markedly reduced after reduction and alkylation, which resulted in disruption of the single disulfide bond between Cys17 and Cys38. Moreover, peptides derived from other regions of CGA and CGB, which included CGA-(403-428), CGB-(1-16), CGB-(316-326), and CGB-(635-657) were inactive. Pulse-chase experiments, using primary cultures of bovine parathyroid cells, revealed the presence of a CGA peptide in the culture medium that had the same amino-terminal sequence and mobility on sodium dodecyl sulfate-polyacrylamide gels as synthetic CGA-(1-76). Furthermore, in binding and cross-linking studies using intact parathyroid cells, CGA-(1-40) formed a single, covalently linked protein complex with a mol wt of 78,000. Formation of the protein complex could be completely inhibited in the presence of an excess of either CGB-(1-41) or CGA-(17-38). These results show that a naturally occurring amino-terminal peptide from CGA as well as shorter analogs can act as potent inhibitors of PTH secretion, and that their biological activity may be mediated through binding to a specific cell surface protein.
The distribution of secretoneurin, a peptide derived from its precursor secretogranin II by proteolytic processing, was studied in the central nervous system of the rat by immunocytochemistry and radioimmunoassay and compared to the distribution of secretogranin II messenger RNA by using in situ hybridization. With a specific antiserum a distinct staining of fibers and to a lesser extent also of perikarya was observed throughout the central nervous system. A high density of immunoreactive fibers and terminals was found in several brain areas, i.e. the lateral septum, the medial parts of the amygdala, some medial thalamic nuclei, the hypothalamus, habenula, nucleus interpeduncularis, locus coeruleus, nucleus tractus solitarii, the substantiae gelatinosae of the caudal trigeminal nucleus and of the spinal cord. The quantitative distribution as measured by a radioimmunoassay agreed well with the varying densities of immunoreactivity found by immunocytochemistry. The highest concentrations of this peptide were present in the hypothalamus, in particular, in the median eminence and are comparable to those of the most highly concentrated neuropeptides. The distribution of immunopositive perikarya corresponded well with that of secretogranin II messenger RNA obtained by in situ hybridization. The pattern of secretoneurin expression in rat brain was widespread and unique, partially overlapping with established chemical transmitters and neuropeptides. The functional significance of this new brain peptide remains to be established.
Secretogranin II (chromogranin C), originally described as tyrosine sulfated protein of the anterior pituitary, is present in large dense core vesicles of several endocrine cells and neurons. We raised antisera in rabbits to conjugates of two synthetic peptides (bovine secretogranin 133-151 and rat secretogranin 154-186) flanked in the primary structure of secretogranin II by pairs of basic residues and used them to investigate the proteolytic processing of this protein by immunoblotting and a newly developed radioimmunoassay. The sensitivity of this assay was 30 fmol for secretogranin 154-186 and 60 fmol for secretogranin 133-151. The highest degree of processing of secretogranin II (> 90%) occurs in brain. One of the peptides (secretogranin 133-151) is not generated to any significant extent. The other peptide, secretogranin 154-186, however, is formed in vivo, and in brain the free peptide apparently represents the predominant form. The highest concentrations of secretogranin 154-186 are found in the hypothalamus, two- to six-fold lower levels are present in the hippocampus, caudate nucleus, thalamus and brainstem. These concentrations are comparable to those of established neuropeptides. In order to indicate the special relevance of secretogranin II and of this peptide for brain we have named this peptide secretoneurin. The newly developed radioimmunoassay for this peptide will be a useful tool to establish its physiologic role in brain.
Pustulosis palmoplantaris (PPP) is a common chronic skin disease, which is very resistant to treatment. It is not known why the lesions are located in the palms and soles. There are few studies of the disease and in particular studies of the histology. Fifty-nine patients with PPP answered a questionnaire concerning their medical history and 39 of them were clinically examined. Biopsy specimens were taken from involved skin in 22 of the 39 patients and studied immunohistologically for tryptase+ mast cells, EG2+ eosinophils, lipocalin+ neutrophils and CD3+ T lymphocytes. The sweat gland and sweat duct were visualized with AE1/AE3 antibody (cytokeratins 1-8, 10, 14/15, 16, 19). In addition to neutrophils in the pustule and lymphocytes in the upper dermis, there were also large numbers of mast cells and eosinophils in the subpustular area. Numerous eosinophils were present in the pustule. The epidermal part of the eccrine duct was not detectable in any of the specimens from patients with PPP but was present in all of the nine control persons (including two smokers). The results indicate that the acrosyringium is involved in the inflammation and also that mast cells and eosinophils participate in a hitherto unknown way. Of the 39 patients clinically examined, two had previously diagnosed thyroid disease and two had gluten hypersensitivity. Seventeen had one or several abnormal serum concentrations of thyroid-stimulating hormone, thyroxin, antibodies against thyroglobulin or thyroperoxidase and 10 had immunoglobulin (Ig) A antibodies to gliadin. The mean +/- SD for serum IgA and for eosinophil cationic protein was increased. From the questionnaire the most notable finding was that 56 of the 59 patients had been or still were smokers, all of whom had started smoking before the first signs of PPP. We hypothesize that the acrosyringium might be the target for the inflammation and that PPP is linked to autoimmune thyroid disease and smoking.
Patients with palmoplantar pustulosis (PPP) frequently report that stress worsens their condition. A study was therefore made of the distribution and number of nerve fibres positive for protein gene product (PGP) 9.5 (a general nerve marker) and nerve fibres with substance P- and calcitonin gene-related peptide-like immunoreactivity in involved skin from patients with PPP and in skin from healthy controls. The number of mast cells in the papillary dermis was larger (P = 0.0003) in lesional palmar PPP skin than in control skin, and the number of contacts between mast cells and nerve fibres was significantly larger (P = 0.02) in PPP skin than in control skin. Image analysis of the nerve fibres around the sweat glands showed that the positively stained area as a percentage of the total area of the sweat gland (coil + surrounding nerves) was significantly lower in PPP skin (P = 0.0006). Furthermore, the nerves seemed to be fragmented. Neutrophils within and below the pustules and in the papillary dermis showed positive substance P staining. The increased number of contacts between nerves and mast cells in PPP skin and the intense substance P-like immunoreactivity of the neutrophils indicate that neuromediation may influence the inflammation in PPP, whereas the destruction of the nerve fibres around the sweat glands might be a result of the inflammation.
Angiotensin II exerts its actions through its specific receptors. However, expression of these receptors has not been determined in sweat glands.
To clarify the expression and localization of the angiotensin receptors in normal human sweat glands and eccrine poroma.
Expression of angiotensin type 1 (AT1) and type 2 (AT2) receptors in normal human eccrine and apocrine sweat glands and 12 cases of eccrine poroma was studied using immunohistochemistry.
In eccrine sweat glands, the acrosyringium and the inner surfaces and luminal cells of the intradermal duct showed positive staining with AT1. In apocrine sweat glands, the intraepithelial duct and luminal cells of the intradermal duct showed positive staining with AT1. In 12 cases of eccrine poroma, some of the tumour cells in the tumour strands and cells surrounding the luminal structures stained positively. There were no positive findings with AT2.
Studying AT1 distribution may be useful in understanding the pathophysiology of sweat glands and sweat gland tumours.
Studies in mammalian skin have shown expression of the genes for corticotropin-releasing hormone (CRH) and the related urocortin peptide, with subsequent production of the respective peptides. Recent molecular and biochemical analyses have further revealed the presence of CRH receptors (CRH-Rs). These CRH-Rs are functional, responding to CRH and urocortin peptides (exogenous or produced locally) through activation of receptor(s)-mediated pathways to modify skin cell phenotype. Thus, when taken together with the previous findings of cutaneous expression of POMC and its receptors, these observations extend the range of regulatory elements of the hypothalamic-pituitary-adrenal axis expressed in mammalian skin. Overall, the cutaneous CRH/POMC expression is highly reactive to common stressors such as immune cytokines, ultraviolet radiation, cutaneous pathology, or even the physiological changes associated with the hair cycle phase. Therefore, similar to its central analog, the local expression and action of CRH/POMC elements appear to be highly organized and entrained, representing general mechanism of cutaneous response to stressful stimuli. In such a CRH/POMC system, the CRH-Rs may be a central element.
Secretoneurin (SN), a newly discovered neuropeptide, may be implicated in inflammatory responses as it was shown to modulate leukocyte, endothelial and mesenchymal cell functions. Neutrophils placed above pulmonary arterial or venous endothelial monolayers migrated through this cellular barrier in response to apical or basal stimulation with SN in a dose-dependent manner. At optimal concentrations of 10(-6) to 10(-8) M, SN was nearly equally effective in stimulating neutrophil transmigration as was tumor necrosis factor-alpha at 10 ng/ml or a chemotactic gradient of formyl-Met-Leu-Phe (10(-8) M). Stimulation of transendothelial migration appears to be specific, since a trypsin digest of SN was ineffective and excess concentrations of anti-SN antibodies completely abolished the effect. Inhibition of cyclooxygenase or nitric oxide synthase did not affect the action of SN. Preincubation of endothelial cells with pertussistoxin (PTx) or choleratoxin (CTx), and the presence of staurosporine significantly inhibited transmigration, suggesting that SN uses a signalling pathway that is coupled to G-proteins and protein kinase C in endothelium. Moreover, SN treatment resulted in transient elevation of cytoplasmatic calcium concentration in endothelial cells. These data support the hypothesis that SN might contribute to neurogenic inflammation in vivo and reveal signalling mechanisms of SN in endothelial cells.
The eccrine gland is one of the major cutaneous appendages and secretes sweat. Its principal function is thermoregulation during exposure to a hot environment or physical exercise. In addition to this function, we show that LL-37, a member of cathelicidin family of anti-microbial peptides, is expressed in sweat. LL-37 protein and mRNA was seen in the eccrine structures of normal human skin by immunohistochemistry and in situ hybridization. LL-37 was localized to both the eccrine gland and sweat ductal epithelial cells, whereas dermcidin, a previously described natural antibiotic in sweat, was expressed only in the gland itself. The anti-microbial activity of LL-37 and dermcidin against various bacteria in the sweat ionic environment was demonstrated by solution colony forming assay using synthetic peptides, and in sweat obtained from normal volunteers. These results indicate that cathelicidin is secreted in human sweat, has potent anti-microbial activity against both gram-positive and gram-negative bacteria, and can, after processing from the preproform, provide a barrier for protection against infection. Thus, sweat represents a unique mode of delivery for potent innate immune effector molecules in the absence of inflammation.
The members of the chromogranin–secretogranin family of peptide hormones, biogenic amines, and neurotransmitters are enclosed within vesicles in the neuroendocrine system and a variety of neurons. These granins, the chief of which is chromogranin A, participate in sympathoadrenal activity and serve as markers of neuroendocrine tumors, especially pheochromocytoma.
To get more insight into the differentiation patterns of pancreatic islet neuroendocrine cells and granules during ontogeny, the expression and localization of chromogranin A (CgA), chromogranin B (CgB), synaptophysin, and insulin were ultrastructurally studied with the immunogold technique in porcine and human pancreatic islet neuroendocrine cells.
In porcine pancreas at early fetal stage, CgA was visualized throughout the immature granules in all neuroendocrine cells. Later, CgB also was expressed with the same pattern in most granules in all types of cells. In neonatal islets, CgA was localized in the periphery of immature alpha- and beta-cell granules and throughout the matrix of delta-cell granules; CgB was distributed throughout the matrix of these granules. In adult islets, alpha-cell granules stored CgA in the halo and CgB in both the core and the halo, beta-cell granules stored both CgA and CgB in their cores, and in delta-cell granules, both substances were mixed throughout the matrix. In all ontogenetic stages, synaptophysin was demonstrated in all cell types and granules. Insulin was expressed in early fetal cells of both pigs and humans, and colocalization with CgA, CgB, and synaptophysin was demonstrated.
The early expression of CgA and synaptophysin may reflect a role at early fetal stages, and the individual localization of CgA and CgB upon differentiation indicates individual functions.
The chromogranins A (CgA) and B (CgB) and secretogranin II (SgII) constitute the main members of a family of uniquely acidic secretory proteins in elements of the diffuse neuroendocrine system. These genetically distinct proteins, CgA, CgB, SgII and the less well known secretogranins III–VII are collectively referred to as‘granins’and characterised by numerous pairs of basic amino acids as potential cleavage sites for processing by the co‐stored prohormone converting enzymes PC 1/3 and PC2.
This review is directed towards comparative and functional aspects of the granins with emphasis on their phylogenetically conserved sequences. Recent developments provide ample evidence of widely different effects and targets for the intact granins and their derived peptides, intracellularly in the directed trafficking of storage components during granule maturation and extracellularly in autocrine, paracrine and endocrine interactions. Most of the effects assigned to the granin derived peptides fit into patterns of direct or indirect inhibitory modulations of major functions. So far, peptides derived from CgA (vasostatins, chromacin, pancreastatin, WE‐14, catestatin and parastatin), CgB (secretolytin) and SgII (secretoneurin) are the most likely candidates for granin‐derived regulatory peptides, of postulated relevance not only for homeostatic processes, but also for tissue assembly and repair, inflammatory responses and the first line of defence against invading microorganisms.
Secretoneurin (SN) represents a 33 amino acid neuropeptide, which is highly conserved between mammals, reptiles, birds, amphibians and fish. It is specifically expressed in endocrine, neuroendocrine and neuronal tissues. In brain, the pattern of SN expression is widespread and unique, partially overlapping with established neurotransmitters. ProSN, the precursor protein, also named secretogranin II, belongs to a class of proteins collectively called chromogranins. Changes in ProSN mRNA, which is significantly regulated by cell depolarisation, represent a useful marker for both rapid and long-lasting changes (positive and negative) of neuronal activity. Under pathophysiological conditions, especially following cellular hypoxia, SN expression can be induced in non-endocrine tissues like muscle cells, pneumocytes or tumor epithelial cells. Several biological effects were attributed to SN. SN releases dopamine from rat striatal slices in a dose dependent manner and influences neurite outgrowth in the developing cerebellum. It potently and specifically attracts monocytes, eosinophils and endothelial cells towards a concentration gradient and acts as an angiogenic cytokine comparable in potency to VEGF. Thus, SN contributes to neurogenic inflammation and might play a role in the (hypoxia-driven) induction of neo-vascularisation in ischemic diseases like peripheral or coronary artery disease, diabetic retinopathia, cerebral ischemia or in solid tumors. The signalling pathways of various biological effects have not been identified in detail, but most data point to a G-protein coupled receptor structure with respective associated intracellular events.
Cotricotropin-releasing hormone (CRH) and related peptides are produced in skin that is dependent on species and anatomical location. Local peptide production is regulated by ultraviolet radiation (UVR), glucocorticoids and phase of the hair cycle. The skin also expresses the corresponding receptors (CRH-R1 and CRH-R2), with CRH-R1 being the major receptor in humans. CRH-R1 is expressed in epidermal and dermal compartments, and CRH-R2 predominantly in dermal structures. The gene coding for CRH-R1 generates multiple isoforms through a process modulated by UVR, cyclic adenosine monophosphate (cAMP) and phorbol 12-myristate 13-acetate. The phenotypic effects of CRH in human skin cells are largely mediated by CRH-R1alpha through increases in concentrations of cAMP, inositol triphosphate (IP3), or Ca2+ with subsequent activation of protein kinases A (PKA) and C (PKC) dependent pathways. CRH also modulates the activity of nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-kappaB), activator protein 1 (AP-1) and cAMP responsive element binding protein (CREB). The cellular functions affected by CRH depend on cell type and nutritional status and include modulation of differentiation program(s), proliferation, viability and immune activity. The accumulated evidence indicates that cutaneous CRH is also a component of a local structure organized similarly to the hypothalamo-pituitary-adrenal axis.
Psychological stress is known to aggravate inflammatory skin diseases such as atopic dermatitis, psoriasis and contact sensitivity by altering the cellular constituents of the immune system. The skin appendages function dually as prominent targets and sources of the peripheral corticotropin-releasing hormone-proopiomelanocortin (CRH-POMC) axis. In this study, we examined the expression level of CRH-POMC axis constituents in psoriasis, a well-known stress-related inflammatory skin disease. The 15 psoriasis patients and six normal controls were retrospectively selected after extensive review of their clinical records and skin biopsy specimens. We immunohistochemically analysed the expressivity of CRH, adrenocorticotrophic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH) in various types of psoriatic lesions and control skin. A significant increase of CRH expression was observed in psoriatic lesions, which involved the entire epidermis (upper layer in particular), hair follicles and sweat glands compared with controls. Expression of ACTH and alpha-MSH was clearly stimulated in a subset of psoriasis patients compared with controls, but on the whole, lacked statistical significance. The immunoreactivity of CRH, ACTH and alpha-MSH in psoriasis was not dependent on its clinical subtype, duration or number of previous treatments. Compared with the definite increase of CRH expression in psoriasis, the expression of the POMC peptides was heterogenous with no overall significance. From the findings, we suggest that CRH, a key stress hormone, may play an important role in the pathomechanism of psoriasis.
Palmoplantar pustulosis (PPP) is probably the inflammatory skin disease most strongly associated to smoking. The disease is common in middle-aged, smoking women, and is chronic, sometimes disabling and characterized by pustules, erythema and scaling on the soles and palms. It is often treatment-resistant. PPP patients have a co-morbidity with an increased risk of autoimmune thyroid disease, celiac disease/gluten intolerance, abnormal calcium homeostasis, diabetes type 2, and depression. The sweat gland apparatus is involved in the pathogenesis of PPP since a) the normal structure of the acrosyringium is abolished so the keratin pattern differs to that in normal palmar skin; b) granulocytes migrate outwards in the acrosyringium forming the pustule in the stratum corneum. Acetylcholine (ACh) is the main inducer of sweating. With immunohistochemistry the ACh synthesizing enzyme choline acetyltransferase (ChAT) and the ACh-degrading enzyme acetylcholinesterase (AChE) were found to be strongly expressed in the gland and duct as were the alpha-3 and alpha-7 nicotinic acetylcholine receptors (nAChRs). Smoking influenced the staining intensity of the enzymes and the alpha-3 nAChR in healthy subjects. In involved PPP skin there was a massive infiltration of granulocytes expressing ChAT and alpha-3 nAChR, and mast cells expressing AChE indicating a role for acetylcholine in inflammation. Cessation of smoking resulted in fewer pustules, and less scaling and erythema. The mechanisms for the effect of nicotine/smoking in PPP are still unknown but nicotine may lead to enhanced inflammation in consideration of the properties of the sweat duct and/or nicotine might facilitate autoimmune reactions.
Novel auto-crine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholin-ergic antagonist
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