Nataliya M Kushnir-Sukhov’s research while affiliated with National Institute of Dental and Craniofacial Research, National Institutes of Health and other places

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Publications (13)


Bone Marrow Stromal Cells Inhibit Mast Cell Function Via a COX2 Dependent Mechanism
  • Article

April 2011

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66 Reads

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116 Citations

Clinical & Experimental Allergy

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Nataliya M. Kushnir-Sukhov

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Mast cells (MCs) have a central role in the induction of allergic inflammation, such as seen in asthma, and contribute to the severity of certain autoimmune diseases, such as rheumatoid arthritis. The MC thus represents an important inflammatory cell, and one which has resisted therapeutic attempts to alter its role in disease. Because bone marrow-derived stromal cells (BMSC, also known as mesenchymal stem cells or MSCs) have been reported to alter allergic inflammation in vivo, we chose to study the interaction between mouse BMSC and mouse bone marrow-derived MCs. MC degranulation, cytokine production and chemotaxis were evaluated in vitro following co-culture with BMSCs either in cell contact or a transwell. In addition, MC degranulation was assessed in vivo following administration of BMSCs in a model of passive cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms of MC suppression by BMSCs were determined through use of inhibitors or antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3-dioxygenase, EP1-4 receptors, TGF-β and IL-10. Lastly, we utilized either BMSCs or MCs deficient in COX1, COX2 or EP1-4 receptors to confirm the mechanisms of inhibition of MC function by BMSCs. We discovered that BMSCs will effectively suppress specific MC functions in vitro as well as in vivo. When MCs are cocultured with BMSCs to allow cell-to-cell contact, BMSCs suppressed MC degranulation, pro-inflammatory cytokine production, chemokinesis and chemotaxis. Similarly, MC degranulation within mouse skin or the peritoneal cavity was suppressed following in vivo administration of BMSCs. Further, we found that these inhibitory effects were dependent on up-regulation of COX2 in BMSCs; and were facilitated through the activation of EP4 receptors on MCs. These observations support the concept that BMSCs have the ability to suppress MC activation and therefore could be the basis for a novel cell based therapeutic approach in the treatment of MC driven inflammatory diseases.


Mastocytosis

February 2009

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12 Reads

Mastocytosis is characterized by the abnormal growth and accumulation of mast cells in one or more organ systems and may vary significantly in clinical presentation and severity. The disease is unusual, is known to affect both males and females in all age groups, and in most cases is not inherited. While knowledge of mast cell growth and differentiation has advanced tremendously since this cell was discovered by Ehrlich in 1878, the explanation for the basis of mastocytosis in all its variants is only partially understood. In most instances, however, systemic mastocytosis is now considered a clonal disorder of the hematopoietic system, and in the majority of cases follows a benign course. The diagnosis of systemic mastocytosis is challenging, especially in the absence of cutaneous involvement. Manifestations of the disease are provoked in part by the resultant increase in mast cell-derived mediators, which leads to a variety of local and systemic effects. Most patients with mastocytosis have indolent disease and are managed symptomatically using treatments directed toward mast cell mediator-related symptoms. Such patients have a normal lifespan with minimal limitations. Cases of aggressive mastocytosis, on the other hand, may lead to disability or even death. Cases of mast cell disease diagnosed in childhood often resolve by adulthood, while adult-onset mastocytosis usually persists. Mastocytosis is variable in respect to the organ systems involved, clinical presentation, symptoms, and association with other hematologic diseases. This has suggested the need for an improved classification scheme to allow assessment of prognosis and therapy. The heterogeneity of the disease patterns in mastocytosis strongly suggests that more than one biological lesion may occur in the developmental sequence that leads to placement of mast cells in tissues. The diagnosis is now aided by new surrogate markers. Therapy of mastocytosis is mainly symptomatic and palliative. At the molecular level, recent studies have reinforced the role of activating mutations in Kit in the etiology of mastocytosis. These findings provide a conceptual basis for the development of new therapeutic strategies.


Clinical correlates of blood serotonin levels in patients with mastocytosis

January 2009

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462 Reads

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42 Citations

European Journal of Clinical Investigation

Mastocytosis is a clonal disorder associated with an increased mast cell burden. We have recently demonstrated the ability of human mast cells to express and be activated through multiple serotonin receptors; to synthesize and release serotonin; and that mastocytosis patients may have abnormal serotonin levels. As serotonin has been implicated in the genesis of clinical symptoms found in association with some chronic diseases, we have now determined the whole blood serotonin levels in 29 patients diagnosed with mastocytosis, and correlated these levels with multiple clinical and laboratory parameters. Patients with mastocytosis were categorized according to disease variant. Blood serotonin values were determined and correlated with values reported for normal subjects; and clinical and laboratory features of the disease. Total blood serotonin levels followed a bimodal distribution in line with our earlier report, unlike the normal distribution reported for normal individuals. Serotonin levels did not correlate with platelet numbers, liver function tests or serum tryptase levels. Patients with lower serotonin values had greater rates of fatigue (P = 0.0001), migraine headaches (P = 0.0028), psychiatric symptoms (P = 0.0001), diarrhoea (P = 0.0407), flushing (0.0085), and abdominal and bone pain (P = 0.0001). Our study suggests that low blood serotonin levels help define a sub-group of patients with mastocytosis that are more likely to present with neurological and gastrointestinal complaints, and suggests that the use of pharmacologic agents that alter blood serotonin levels could be explored in selected patients.


Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis
  • Article
  • Full-text available

November 2007

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140 Reads

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230 Citations

Blood

Idiopathic anaphylaxis remains a perplexing disorder in which existing prophylactic therapy is inadequate. In this prospective study, we sought to determine whether patients with idiopathic anaphylaxis might have evidence for a clonal disorder of mast cells related to mastocytosis and for which novel targeted therapies might be considered. We report 12 patients with "idiopathic" anaphylaxis who did not exhibit either urticaria pigmentosa or the characteristic bone marrow biopsy finding of multifocal mast-cell aggregates observed in systemic mastocytosis. Of these 12 patients, 5 had evidence of 1 or more minor criteria for mastocytosis. C-KIT mutational analysis was positive for the 816D>V activating mutation in 3 of 3 patients in CD25(+) bone marrow cells where the analysis was performed. These results demonstrate the presence of an aberrant mast-cell population carrying clonal markers in a subset of patients diagnosed with "idiopathic" anaphylaxis, who may respond to inhibitors targeting mutated C-KIT. This intramural clinical trial was conducted in 2003 and 2004 and was registered at (http://clinicalcenter.nih.gov) with a study number 03-I-0010. Since the study is now closed, it is no longer available online.

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FIGURE 2. 
FIGURE 3. 
FIGURE 4. 
FIGURE 5. Ionizing gamma radiation induces ROS production in BMMC. A, ROS production in BMMC exposed to 50 and 400 cGy of gamma radiation. BMMC were loaded with the fluorescent probe DCF, and intracellular ROS was measured immediately after exposure of BMMC to gamma radiation. B, Area under the curve (AUC) representation of total ROS production in irradiated BMMCs as compared with nonirradiated cells. Ionomycin was used to generate a positive control. Values are the average SEM of three independent experiments performed in triplicate. p 0.001.
FIGURE 7. 

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Effects of Gamma Radiation on FcεRI and TLR-Mediated Mast Cell Activation1

September 2007

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97 Reads

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40 Citations

The Journal of Immunology

Ionizing gamma radiation has several therapeutic indications including bone marrow transplantation and tumor ablation. Among immune cells, susceptibility of lymphocytes to gamma radiation is well known. However, there is little information on the effects of gamma radiation on mast cells, which are important in both innate and acquired immunity. Previous studies have suggested that mast cells may release histamine in response to high doses of gamma radiation, whereas other reports suggest that mast cells are relatively radioresistant. No strong link has been established between gamma radiation and its effect on mast cell survival and activation. We examined both human and murine mast cell survival and activation, including mechanisms related to innate and acquired immune responses following gamma radiation. Data revealed that human and murine mast cells were resistant to gamma radiation-induced cytotoxicity and, importantly, that irradiation did not directly induce β-hexosaminidase release. Instead, a transient attenuation of IgE-mediated β-hexosaminidase release and cytokine production was observed which appeared to be the result of reactive oxygen species formation after irradiation. Mast cells retained the ability to phagocytose Escherichia coli particles and respond to TLR ligands as measured by cytokine production after irradiation. In vivo, there was no decrease in mast cell numbers in skin of irradiated mice. Additionally, mast cells retained the ability to respond to Ag in vivo as measured by passive cutaneous anaphylaxis in mice after irradiation. Mast cells are thus resistant to the cytotoxic effects and alterations in function after irradiation and, despite a transient inhibition, ultimately respond to innate and acquired immune activation signals.



Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

February 2007

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239 Reads

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97 Citations

American Journal of Respiratory Cell and Molecular Biology

Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.Cg-kit(W-sh) mast cell-deficient mice. B6.Cg-kit(W-sh) mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow-derived mast cells (BMMC), including degranulation (beta-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on Fc epsilon RI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-alpha, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after Fc epsilon RI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF-alpha production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis.



FIGURE 2. Effects of 5-HT on mBMMC adhesion to fibronectin in the presence or absence of SCF. mBMMC adhesion was analyzed using 96-well fibronectin-precoated plates. Cells (5 10 4 /well) were treated with various concentrations of 5-HT alone or in combination with SCF. Spontaneous adhesion was subtracted from all data sets. Effect of 5-HT alone (A) or in the presence of 1 ng/ml (B), 10 ng/ml (C), or 100 ng/ml (D) SCF. Values of p were calculated by two-way ANOVA; dose-dependent differences were assessed by Bonferroni's posthoc test or Student's t test. , p 0.05; , p 0.01, 5-HT vs spontaneous; #, 0.05; ###, 0.001, SCF vs spontaneous; , 0.05, 5-HT/SCF vs SCF alone. Data are represented as mean SEM (n 3-5).
5-Hydroxytryptamine Induces Mast Cell Adhesion and Migration

December 2006

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145 Reads

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139 Citations

The Journal of Immunology

The neurotransmitter serotonin (5-hydroxytryptamine (5-HT)) is implicated in enhancing inflammatory reactions of skin, lung, and gastrointestinal tract. To determine whether 5-HT acts, in part, through mast cells (MC), we first established that mouse bone marrow-derived MC (mBMMC) and human CD34(+)-derived MC (huMC) expressed mRNA for multiple 5-HT receptors. We next determined the effect of 5-HT on mouse and human MC degranulation, adhesion, and chemotaxis. We found no evidence that 5-HT degranulates MC or modulates IgE-dependent activation. 5-HT did induce mBMMC and huMC adherence to fibronectin; and immature and mature mBMMC and huMC migration. Chemotaxis was accompanied by actin polymerization. Using receptor antagonists and pertussis toxin, we identified 5-HT(1A) as the principal receptor mediating the effects of 5-HT on MC. mBMMC from the 5-HT(1A) receptor knockout mouse (5-HT(1A)R(-/-)) did not respond to 5-HT. 5-HT did induce accumulation of MC in the dermis of 5-HT(1A)R(+/+) mice, but not in 5-HT(1A)R(-/-) mice. These studies are the first to demonstrate an effect of 5-HT on MC. Furthermore, both mouse and human MC respond to 5-HT through the 5-HT(1A) receptor. Our data are consistent with the conclusion that 5-HT promotes inflammation by increasing MC at the site of tissue injury.


Elevated Tryptase Levels Are Associated with Greater Bone Density in a Cohort of Patients with Mastocytosis

March 2006

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112 Reads

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43 Citations

International Archives of Allergy and Immunology

Mastocytosis is associated with a pathological increase in tissue mast cells. Associated skeletal problems include a decrease in bone density and pathological fractures. In order to explore the relationship between bone density and the severity of mastocytosis, 21 patients with mastocytosis who underwent dual-energy X-ray absorptiometry were entered into this study. Correlation coefficients were computed between Z-scores and demographic, clinical and laboratory data. Femoral neck Z-scores correlated with serum tryptase levels when all the patients were considered (p=0.029). Patients with less severe disease had significantly lower values at the L1-L4 spine (p=0.046) and femoral neck (p=0.029) Z-scores compared to patients with more severe disease. Most patients who had low Z-scores (between -1 and -2.5) were under 50 years of age, had less severe disease and had lower serum tryptase levels. A history of gastroesophageal reflux disease and a history of hypotensive episodes correlated with lower L1-L4 spine Z-scores (p<0.05). Thus, patients with less severe disease and lower serum tryptase levels should in particular have their bone density determined with treatment appropriate to the findings.


Citations (9)


... However, the heterogeneity of mast cells lies also in their ontogeny, and likely arises from their origins during early development or adulthood as well as the stimuli they receive, potentially in ways that are not yet fully characterized. Some mast cells, although not their precursors, are radioresistant and long-lived, possibly surviving for years in certain tissues 23 . In addition, they have dynamic responses to infections and inflammatory stimuli, being capable of local proliferation in some circumstances as well as survival and regranulation following activation, which contrasts with the propensity of many immune cells to undergo apoptosis after activation. ...

Reference:

New perspectives on the origins and heterogeneity of mast cells
Effects of Gamma Radiation on FcRI and TLR-Mediated Mast Cell Activation
  • Citing Article

... The pathogenesis of mastocytosis post-radiation therapy remains unknown. One explanation, based on in-vitro experiments, suggests that ionizing radiation promotes skin fibrosis, as it signals degranulation and subsequent tryptase secretion by mast cells, which are known to be radioresistant [15,16]. Another theory is that mast cell infiltration reflects a koebnerization response to trauma, accounting for why the inflammation is usually confined to the borders of irradiated areas [5]. ...

Effects of Gamma Radiation on FcεRI and TLR-Mediated Mast Cell Activation1

The Journal of Immunology

... This compound leads to the differentiation of dendritic cells to an anti-inflammatory phenotype, suppresses the mast cells' inflammatory response (MC), and increases the production of M2 macrophages. 34, 115 In a mouse asthma model, injecting MSCs derived from mouse adipose tissue increased lung TGF-β and PGE2 and improved lung function. 116 Inhibits the production of PGE2, TGF-β, and MSC-induced Tregs, and abolishes the immunosuppressive effects of mouse adipose tissue-derived MSCs in asthma. ...

Bone Marrow Stromal Cells Inhibit Mast Cell Function Via a COX2 Dependent Mechanism
  • Citing Article
  • April 2011

Clinical & Experimental Allergy

... Data on the ability of human mast cells to synthesize serotonin are controversial. Buhner and Schemann (31) claimed that human mast cells in the mucosal layer of the intestine cannot synthesize 5-HT, contradicting other reports (30,32,33). The possible role of mast cell serotonin can be explained in different ways. ...

Clinical correlates of blood serotonin levels in patients with mastocytosis
  • Citing Article
  • January 2009

European Journal of Clinical Investigation

... www.nature.com/scientificreports/ are typically present in ISM, osteosclerosis is more frequently identified in AdvSM 26,27 . We recently showed that an increased BMD is strongly associated with advanced disease and inferior outcome 19 . ...

Elevated Tryptase Levels Are Associated with Greater Bone Density in a Cohort of Patients with Mastocytosis
  • Citing Article
  • March 2006

International Archives of Allergy and Immunology

... MCs not only recruit and activate other immune cells by secreting inflammatory mediators but also regulate vascular permeability, smooth muscle cell contraction, and fibroblast growth in lung fibrosis (Wygrecka et al., 2013). Jared et al. found that, unlike wild-type C57BL/6 mice, MC-deficient mice do not develop inflammation nor do they display significant collagen deposition following silica instillation (Brown et al., 2007). MCs also secrete tryptase, which interacts with multiple regulatory factors, such as activating proteinase-activated receptor 2 (PAR2), inducing DNA synthesis in resting fibroblasts and promoting collagen synthesis, thereby stimulating fibroblast proliferation (Henriques Á et al., 2016). ...

Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

American Journal of Respiratory Cell and Molecular Biology

... It can influence the function of various immune cells. For example, mast cell 5-HT is a chemoattractant for eosinophils (34,35). Dendritic cells and monocytes can be activated by serotonin via the 5-HT3, 5-HT4, and 5-HT7 receptors to secrete interleukins (36,37,38) and to promote inflammation (39,40). ...

5-Hydroxytryptamine Induces Mast Cell Adhesion and Migration

The Journal of Immunology

... Histamine, NPFF, and serotonin are released from mast cells upon degranulation and play essential roles in allergy. [44][45][46][47][48][49] We further examined whether MrgprC11 + sensory neurons mediate sneezing associated with allergic rhinitis. Utilizing the mouse models of acute and chronic allergic rhinitis, 15 we found that ablation of MrgprC11 + neurons significantly reduced allergic sneezing ( Figures 3D and 3E). ...

Human mast cells are capable of serotonin synthesis and release
  • Citing Article
  • March 2007

Journal of Allergy and Clinical Immunology

... Idiopathic anaphylaxis is a severe, life-threatening allergic reaction characterized by the sudden onset of symptoms without an identifiable external trigger (4,5). Unlike typical anaphylaxis, which is triggered by known allergens such as foods, insect stings, or medications (1,2), IA presents a significant diagnostic and management challenge due to its unpredictable nature. ...

Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis

Blood