Richard L Gallo

Publications of Richard L Gallo

• T(H)2 cytokines increase kallikrein 7 expression and function in patients with atopic dermatitis.

  Authors: Shin Morizane, Kenshi Yamasaki, Ai Kajita, Kazuko Ikeda, Maosheng Zhan, Yumi Aoyama, Richard L Gallo, Keiji Iwatsuki

  The Journal of allergy and clinical immunology. 04/2012;

• Lack of Neutrophil-Derived CRAMP Reduces Atherosclerosis in Mice.

  Authors: Yvonne Döring, Maik Drechsler, Sarawuth Wantha, Klaus Kemmerich, Dirk Lievens, Santosh Vijayan, Richard L Gallo, Christian Weber, Oliver Soehnlein

  Circulation research. 03/2012;

  Rationale:Neutrophils have been reported to contribute to early atherosclerotic lesion formation. Mechanisms of neutrophil-driven atherosclerosis remain unclear so far.Objective:Investigation of theRationale:Neutrophils have been reported to contribute to early atherosclerotic lesion formation. Mechanisms of neutrophil-driven atherosclerosis remain unclear so far.Objective:Investigation of the role of the neutrophil granule protein cathelicidin (CRAMP in mouse, LL37 in human) in atherosclerosis.Methods and Results:Compared to Apoe(-/-) mice, Cramp(-/-) Apoe(-/-) mice exhibit reduced lesion sizes with lower macrophage numbers. In atherosclerotic aortas, we could detect CRAMP specifically in neutrophils, but not in monocytes or macrophages. By use of intravital microscopy, CRAMP was found to be deposited by activated neutrophils on inflamed endothelium of large arteries. In this location cathelicidins promote adhesion of classical monocytes and neutrophils, but not nonclassical monocytes in a formyl-peptide receptor-dependent manner.Conclusions:Cathelicidins promote atherosclerosis by enhancement of the recruitment of inflammatory monocytes.

• Antimicrobial peptides in the pathogenesis of psoriasis.

  Authors: Shin Morizane, Richard L Gallo

  The Journal of dermatology. 03/2012; 39(3):225-30.

  One characteristic abnormality of lesional skin in psoriasis is the excessive production of antimicrobial peptides and proteins (AMPs). AMPs typically are small (12-50 amino acids), have positiveOne characteristic abnormality of lesional skin in psoriasis is the excessive production of antimicrobial peptides and proteins (AMPs). AMPs typically are small (12-50 amino acids), have positive charge and amphipathic structure, and are found in all living organisms including mammals, insects, plants and invertebrates. These peptides are best known for their integral role in killing pathogenic microorganisms; however, in vertebrates, they are also capable of modifying host inflammatory responses by a variety of mechanisms. In psoriatic lesions, many AMPs are highly expressed, and especially the associations between psoriasis and cathelicidin, β-defensins or S100 proteins have been well studied. Among them, a cathelicidin peptide, LL-37, has been highlighted as a modulator of psoriasis development in recent years. AMPs had been thought to worsen psoriatic lesions but recent evidence has also suggested the possibility that the induction of AMPs expression might improve aspects of the disease. Further investigations are needed to uncover a previously underappreciated role for AMPs in modulating the immune response in psoriasis, and to improve disease without the risks of systemic immunosuppressive approaches.

• Doxycycline Indirectly Inhibits Proteolytic Activation of Tryptic Kallikrein-Related Peptidases and Activation of Cathelicidin.

  Authors: Kimberly N Kanada, Teruaki Nakatsuji, Richard L Gallo

  The Journal of investigative dermatology. 02/2012;

  The increased abundance and activity of cathelicidin and kallikrein 5 (KLK5), a predominant trypsin-like serine protease (TLSP) in the stratum corneum, have been implicated in the pathogenesis ofThe increased abundance and activity of cathelicidin and kallikrein 5 (KLK5), a predominant trypsin-like serine protease (TLSP) in the stratum corneum, have been implicated in the pathogenesis of rosacea, a disorder treated by the use of low-dose doxycycline. Here we hypothesized that doxycycline can inhibit activation of tryptic KLKs through an indirect mechanism by inhibition of matrix metalloproteinases (MMPs) in keratinocytes. The capacity of doxycycline to directly inhibit enzyme activity was measured in surface collections of human facial skin and extracts of cultured keratinocytes by fluorescence polarization assay against fluorogenic substrates specific for MMPs or TLSPs. Doxycycline did inhibit MMP activity but did not directly inhibit serine protease activity against a fluorogenic substrate specific for TLSPs. However, when doxycycline or other MMP inhibitors were added to live keratinocytes during the production of tryptic KLKs, this treatment indirectly resulted in decreased TLSP activity. Furthermore, doxycycline under these conditions inhibited the generation of the cathelicidin peptide LL-37 from its precursor protein hCAP18, a process dependent on KLK activity. These results demonstrate that doxycycline can prevent cathelicidin activation, and suggest a previously unknown mechanism of action for doxycycline through inhibiting generation of active cathelicidin peptides.Journal of Investigative Dermatology advance online publication, 16 February 2012; doi:10.1038/jid.2012.14.

• Antimicrobial peptides: old molecules with new ideas.

  Authors: Teruaki Nakatsuji, Richard L Gallo

  The Journal of investigative dermatology. 12/2011; 132(3 Pt 2):887-95.

  Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules withAlmost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with antibiotic activity have been isolated from animals, insects, plants, and bacteria, and their use has revolutionized clinical medicine. So far, more than 1,200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears that all living organisms use these antimicrobial peptides (AMPs) in their host defense. In the past decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is because of their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis, and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis, and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field.

• Rosacea as a disease of cathelicidins and skin innate immunity.

  Authors: Kenshi Yamasaki, Richard L Gallo

  The journal of investigative dermatology. Symposium proceedings / the Society for Investigative Dermatology, Inc. [and] European Society for Dermatological Research. 12/2011; 15(1):12-5.

  Rosacea is a common and chronic inflammatory skin disease most frequently seen in groups of genetically related individuals. Although the symptoms of rosacea are heterogeneous, they are all relatedRosacea is a common and chronic inflammatory skin disease most frequently seen in groups of genetically related individuals. Although the symptoms of rosacea are heterogeneous, they are all related by the presence of characteristic facial or ocular inflammation involving both the vascular and tissue stroma. Until recently, the pathophysiology of this disease was limited to descriptions of a wide variety of factors that exacerbate or improve disease. Recent molecular studies show a common link between the triggers of rosacea and the cellular response, and these observations suggest that an altered innate immune response is involved in disease pathogenesis. Understanding rosacea as a disorder of innate immunity explains the benefits of current treatments and suggests new therapeutic strategies for alleviating this disease.

• Montagna Symposium 2010: small molecules: skin as the first line of defense.

  Authors: Richard L Gallo, Molly Kulesz-Martin, Jackie R Bickenbach

  The Journal of investigative dermatology. 11/2011; 131(11):2166-8.

• Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands.

  Authors: Shin Morizane, Kenshi Yamasaki, Beda Mühleisen, Paul F Kotol, Masamoto Murakami, Yumi Aoyama, Keiji Iwatsuki, Tissa Hata, Richard L Gallo

  The Journal of investigative dermatology. 08/2011; 132(1):135-43.

  Here we show that keratinocytes in psoriatic lesional skin express increased Toll-like receptor (TLR) 9 that similarly localizes with elevated expression of the cathelicidin antimicrobial peptideHere we show that keratinocytes in psoriatic lesional skin express increased Toll-like receptor (TLR) 9 that similarly localizes with elevated expression of the cathelicidin antimicrobial peptide LL-37. In culture, normal human keratinocytes exposed to LL-37 increased TLR9 expression. Furthermore, when keratinocytes were exposed to LL-37 and subsequently treated with TLR9 ligands, such as CpG or genomic DNA, they greatly increased production of type I IFNs. This response mimicked observations in the epidermis of psoriatic lesional skin as keratinocytes in psoriatic lesions produce greater amounts of IFN-β than normal skin lacking LL-37. The mechanism for induction of type I IFNs in keratinocytes was dependent on TLR9 expression but not on a DNA-LL-37 complex. These findings suggest that keratinocytes recognize and respond to DNA and can actively participate in contributing to the immunological environment that characterizes psoriasis.

• The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections.

  Authors: Michael D Howell, Peisong Gao, Byung Eui Kim, Leighann J Lesley, Joanne E Streib, Patricia A Taylor, Daniel J Zaccaro, Mark Boguniewicz, Lisa A Beck, Jon M Hanifin, Lynda C Schneider, Tissa R Hata, Richard L Gallo, Mark H Kaplan, Kathleen C Barnes, Donald Y M Leung

  The Journal of allergy and clinical immunology. 07/2011; 128(5):1006-14.

  Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. We sought to determine why a subset of patients with AD have anAtopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. We sought to determine why a subset of patients with AD have an increased risk of disseminated viral skin infections. Human subjects with AD with a history of eczema herpeticum (EH) and various control groups were enrolled. Vaccinia virus (VV) expression was measured by means of PCR and immunofluorescent staining in skin biopsy specimens from each study group after incubation with VV. Transgenic mice with a constitutively active signal transducer and activator of transcription 6 gene (STAT6) were characterized for response to VV skin inoculation. Genotyping for 10 STAT6 single nucleotide polymorphisms (SNPs) was performed in a white patient sample (n = 444). VV gene and protein expression were significantly increased in the skin of patients with EH compared with other subject groups after incubation with VV in vitro. Antibody neutralization of IL-4 and IL-13 resulted in lower VV replication in patients with a history of EH. Mice that expressed a constitutively active STAT6 gene compared with wild-type mice had increased mortality and satellite lesion formation after VV skin inoculation. Significant associations were observed between STAT6 SNPs and EH (rs3024975, rs841718, rs167769, and rs703817) and IFN-γ production. The strongest association was observed for a 2-SNP haplotype (patients with AD with a history of EH vs patients with AD without a history of EH, 24.9% vs 9.2%; P = 5.17 × 10(-6)). The STAT6 gene increases viral replication in the skin of patients with AD with a history of EH. Further genetic association studies and functional investigations are warranted.

• Protecting the boundary: the sentinel role of host defense peptides in the skin.

  Authors: Jamie J Bernard, Richard L Gallo

  Cellular and molecular life sciences : CMLS. 07/2011; 68(13):2189-99.

  The skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity in response to injury or microbial insult. The study of antimicrobialThe skin is our primary shield against microbial pathogens and has evolved innate and adaptive strategies to enhance immunity in response to injury or microbial insult. The study of antimicrobial peptide (AMP) production in mammalian skin has revealed several of the elegant strategies that AMPs use to prevent infection. AMPs are inducible by both infection and injury and protect the host by directly killing pathogens and/or acting as multifunctional effector molecules that trigger cellular responses to aid in the anti-infective and repair response. Depending on the specific AMP, these molecules can influence cytokine production, cell migration, cell proliferation, differentiation, angiogenesis and wound healing. Abnormal production of AMPs has been associated with the pathogenesis of several cutaneous diseases and plays a role in determining a patient's susceptibility to pathogens. This review will discuss current research on the regulation and function of AMPs in the skin and in skin disorders.

• Microbial symbiosis with the innate immune defense system of the skin.

  Authors: Richard L Gallo, Teruaki Nakatsuji

  The Journal of investigative dermatology. 06/2011; 131(10):1974-80.

  Skin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the uniqueSkin protects itself against infection through a variety of mechanisms. Antimicrobial peptides (AMPs) are major contributors to cutaneous innate immunity, and this system, combined with the unique ionic, lipid, and physical barrier of the epidermis, is the first-line defense against invading pathogens. However, recent studies have revealed that our skin's innate immune system is not solely of human origin. Staphylococcus epidermidis, a major constituent of the normal microflora on healthy human skin, acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already present opportunistic pathogens. Our resident commensal microbes produce their own AMPs, act to enhance the normal production of AMPs by keratinocytes, and are beneficial to maintaining inflammatory homeostasis by suppressing excess cytokine release after minor epidermal injury. These observations indicate that the normal human skin microflora protects skin by various modes of action, a conclusion supported by many lines of evidence associating diseases such as acne, atopic dermatitis, psoriasis, and rosacea with an imbalance of the microflora even in the absence of classical infection. This review highlights recent observations on the importance of innate immune systems and the relationship with the normal skin microflora to maintain healthy skin.

• Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.

  Authors: Yvonne Dombrowski, Mark Peric, Sarah Koglin, Claudia Kammerbauer, Christine Göss, David Anz, Maren Simanski, Regine Gläser, Jürgen Harder, Veit Hornung, Richard L Gallo, Thomas Ruzicka, Robert Besch, Jürgen Schauber

  Science translational medicine. 05/2011; 3(82):82ra38.

  The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1βThe proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.

• Reductions in claudin-1 may enhance susceptibility to herpes simplex virus 1 infections in atopic dermatitis.

  Authors: Anna De Benedetto, Mark K Slifka, Nicholas M Rafaels, I-Hsin Kuo, Steve N Georas, Mark Boguniewicz, Tissa Hata, Lynda C Schneider, Jon M Hanifin, Richard L Gallo, David C Johnson, Kathleen C Barnes, Donald Y M Leung, Lisa A Beck

  The Journal of allergy and clinical immunology. 04/2011; 128(1):242-246.e5.

• TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes.

  Authors: Kenshi Yamasaki, Kimberly Kanada, Daniel T Macleod, Andrew W Borkowski, Shin Morizane, Teruaki Nakatsuji, Anna L Cogen, Richard L Gallo

  The Journal of investigative dermatology. 03/2011; 131(3):688-97.

  A diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifestsA diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifests unique inflammatory responses to normal environmental stimuli. We hypothesized that abnormal function of innate immune pattern recognition could explain the enhanced sensitivity of patients with rosacea, and observed that the epidermis of patients with rosacea expressed higher amounts of Toll-like receptor 2 (TLR2) than normal patients. Increased expression of TLR2 was not seen in other inflammatory skin disorders such as atopic dermatitis or psoriasis. Overexpression of TLR2 on keratinocytes, treatment with TLR2 ligands, and analysis of TLR2-deficient mice resulted in a calcium-dependent release of kallikrein 5 from keratinocytes, a critical protease involved in the pathogenesis of rosacea. These observations show that abnormal TLR2 function may explain enhanced inflammatory responses to environmental stimuli and can act as a critical element in the pathogenesis of rosacea.

• The coordinated response of the physical and antimicrobial peptide barriers of the skin.

  Authors: Andrew W Borkowski, Richard L Gallo

  The Journal of investigative dermatology. 02/2011; 131(2):285-7.

  Antimicrobial peptides (AMPs) are an essential and multifunctional element for immune defense of the skin during infection and injury. In this issue, Ahrens et al. characterize the response ofAntimicrobial peptides (AMPs) are an essential and multifunctional element for immune defense of the skin during infection and injury. In this issue, Ahrens et al. characterize the response of β-defensins, a class of AMPs, following acute and chronic challenges to the permeability barrier of the skin. Their findings suggest that the antimicrobial and permeability barriers of the skin are closely linked.

• Passive immunoprotection targeting a secreted CAMP factor of Propionibacterium acnes as a novel immunotherapeutic for acne vulgaris.

  Authors: Pei-Feng Liu, Teruaki Nakatsuji, Wenhong Zhu, Richard L Gallo, Chun-Ming Huang

  Vaccine. 02/2011; 29(17):3230-8.

  Propionibacterium acnes (P. acnes) bacteria play a key role in the pathogenesis of acne vulgaris. Although our previous studies have demonstrated that vaccines targeting a surface sialidase orPropionibacterium acnes (P. acnes) bacteria play a key role in the pathogenesis of acne vulgaris. Although our previous studies have demonstrated that vaccines targeting a surface sialidase or bacterial particles exhibit a preventive effect against P. acnes, the lack of therapeutic activities and incapability of neutralizing secretory virulence factors motivate us to generate novel immunotherapeutics. In this study, we develop an immunotherapeutic antibody to secretory Christie-Atkins-Munch-Peterson (CAMP) factor of P. acnes. Via agroinfiltration, P. acnes CAMP factor was encapsulated into the leaves of radishes. ICR mice intranasally immunized with whole leaves expressing CAMP factor successfully produced neutralizing antibodies that efficiently attenuated P. acnes-induced ear swelling and production of macrophage-inflammatory protein-2. Passive neutralization of CAMP factor enhanced immunity to eradicate P. acnes at the infection site without influencing bacterial growth elsewhere. We propose that CAMP factor is a novel therapeutic target for the treatment of various P. acnes-associated diseases and highlight the concept of neutralizing P. acnes virulence without disturbing the bacterial commensalism in human microbiome.

• Exogenous addition of a C-xylopyranoside derivative stimulates keratinocyte dermatan sulfate synthesis and promotes migration.

  Authors: Jun Muto, Nandita Natasha Naidu, Kenshi Yamasaki, Nathalie Pineau, Lionel Breton, Richard L Gallo

  PloS one. 01/2011; 6(10):e25480.

  As C-Xyloside has been suggested to be an initiator of glycosaminoglycan (GAG) synthesis, and GAGs such as Dermatan sulfate (DS) are potent enhancers of fibroblast growth factor (FGF)--10 action, weAs C-Xyloside has been suggested to be an initiator of glycosaminoglycan (GAG) synthesis, and GAGs such as Dermatan sulfate (DS) are potent enhancers of fibroblast growth factor (FGF)--10 action, we investigated if a C-Xylopyranoside derivative, (C-β-D-xylopyranoside-2-hydroxy-propane, C-Xyloside), could promote DS production by cultured normal human keratinocytes, how this occurs and if C-Xyloside could also stimulate FGF-dependent cell migration and proliferation. C-Xyloside-treated keratinocytes greatly increased secretion of total sulfated GAGs. Majority of the induced GAG was chondroitin sulfate/dermatan sulfate (CS/DS) of which the major secreted GAG was DS. Cells lacking xylosyltransferase enzymatic activity demonstrated that C-Xyloside was able to stimulate GAG synthesis without addition to core proteins. Consistent with the observed increase in DS, keratinocytes treated with C-Xyloside showed enhanced migration in response to FGF-10 and secreted into their culture media GAGs that promoted FGF-10-dependent cellular proliferation. These results indicate that C-Xyloside may enhance epithelial repair by serving as an initiator of DS synthesis.

• Propionibacterium acnes CAMP factor and host acid sphingomyelinase contribute to bacterial virulence: potential targets for inflammatory acne treatment.

  Authors: Teruaki Nakatsuji, De-chu C Tang, Liangfang Zhang, Richard L Gallo, Chun-Ming Huang

  PloS one. 01/2011; 6(4):e14797.

  In the progression of acne vulgaris, the disruption of follicular epithelia by an over-growth of Propionibacterium acnes (P. acnes) permits the bacteria to spread and become in contact with variousIn the progression of acne vulgaris, the disruption of follicular epithelia by an over-growth of Propionibacterium acnes (P. acnes) permits the bacteria to spread and become in contact with various skin and immune cells. We have demonstrated in the present study that the Christie, Atkins, Munch-Peterson (CAMP) factor of P. acnes is a secretory protein with co-hemolytic activity with sphingomyelinase that can confer cytotoxicity to HaCaT keratinocytes and RAW264.7 macrophages. The CAMP factor from bacteria and acid sphingomyelinase (ASMase) from the host cells were simultaneously present in the culture supernatant only when the cells were co-cultured with P. acnes. Either anti-CAMP factor serum or desipramine, a selective ASMase inhibitor, significantly abrogated the P. acnes-induced cell death of HaCaT and RAW264.7 cells. Intradermal injection of ICR mouse ears with live P. acnes induced considerable ear inflammation, macrophage infiltration, and an increase in cellular soluble ASMase. Suppression of ASMase by systemic treatment with desipramine significantly reduced inflammatory reaction induced by intradermal injection with P. acnes, suggesting the contribution of host ASMase in P. acnes-induced inflammatory reaction in vivo. Vaccination of mice with CAMP factor elicited a protective immunity against P. acnes-induced ear inflammation, indicating the involvement of CAMP factor in P. acnes-induced inflammation. Most notably, suppression of both bacterial CAMP factor and host ASMase using vaccination and specific antibody injection, respectively, cooperatively alleviated P. acnes-induced inflammation. These findings envision a novel infectious mechanism by which P. acnes CAMP factor may hijack host ASMase to amplify bacterial virulence to degrade and invade host cells. This work has identified both CAMP factor and ASMase as potential molecular targets for the development of drugs and vaccines against acne vulgaris.

• Development of atopic dermatitis-like skin disease from the chronic loss of epidermal caspase-8.

  Authors: Christopher Li, Samuel Lasse, Pedro Lee, Manando Nakasaki, Shih-Wei Chen, Kenshi Yamasaki, Richard L Gallo, Colin Jamora

  Proceedings of the National Academy of Sciences of the United States of America. 12/2010; 107(51):22249-54.

  Atopic dermatitis is an inflammatory skin disease that affects approximately 20% of children worldwide. Left untreated, the barrier function of the skin is compromised, increasing susceptibility toAtopic dermatitis is an inflammatory skin disease that affects approximately 20% of children worldwide. Left untreated, the barrier function of the skin is compromised, increasing susceptibility to dehydration and infection. Despite its prevalence, its multifactorial nature has complicated the unraveling of its etiology. We found that chronic loss of epidermal caspase-8 recapitulates many aspects of atopic dermatitis, including a spongiotic phenotype whereby intercellular adhesion between epidermal keratinocytes is disrupted, adversely affecting tissue architecture and function. Although spongiosis is generally thought to be secondary to edema, we found that suppression of matrix metalloproteinase-2 activity is sufficient to abrogate this defect. p38 MAPK induces matrix metalloproteinase-2 expression to cleave E-cadherin, which mediates keratinocyte cohesion in the epidermis. Thus, the conditional loss of caspase-8, which we previously found to mimic a wound response, can be used to gain insights into how these same wound-healing processes are commandeered in inflammatory skin diseases.

• Tight junction defects in patients with atopic dermatitis.

  Authors: Anna De Benedetto, Nicholas M Rafaels, Laura Y McGirt, Andrei I Ivanov, Steve N Georas, Chris Cheadle, Alan E Berger, Kunzhong Zhang, Sadasivan Vidyasagar, Takeshi Yoshida [......] Tissa Hata, Lynda C Schneider, Jon M Hanifin, Richard L Gallo, Natalija Novak, Stephan Weidinger, Terri H Beaty, Donald Y M Leung, Kathleen C Barnes, Lisa A Beck

  The Journal of allergy and clinical immunology. 12/2010; 127(3):773-86.e1-7.

  Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs)Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with T(H)2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.