Involvement Of Mast Cells Research Articles

Involvement of interferon γ-producing mast cells in immune responses against melanocytes in vitiligo requires MrgX2 activation.

Increasing evidence indicates that oxidative stress and interferon γ (IFNγ)-driven cellular immune responses are responsible for the pathogenesis of vitiligo. However, the connection between oxidative stress and the local production of IFNγ in early vitiligo remains unexplored. The aim of this study was to identify the mechanism underlying the production of IFNγ by mast cells and its impact on vitiligo pathogenesis. Skin specimens from the central, marginal, and perilesional skin areas of active vitiligo lesions were collected to characterize changes of mast cells, CD8+ T cells, and IFNγ-producing cells. Cell supernatants from hydrogen peroxide (H2O2)-treated keratinocytes (KCs) were harvested to measure levels of soluble stem cell factor (sSCF) and matrix metalloproteinase (MMP)-9. A murine vitiligo model was established using Mas-related G protein-coupled receptor-B2 (MrgB2, mouse ortholog of human MrgX2) conditional knockout (MrgB2-/-) mice to investigate IFNγ production and inflammatory cell infiltrations in tail skin following the challenge with tyrosinase-related protein (Tyrp)-2 180 peptide. Potential interactions between the Tyrp-2 180 peptide and MrgX2 were predicted using molecular docking. The siRNAs targeting MrgX2 and the calcineurin inhibitor FK506 were also used to examine the signaling pathways involved in mast cell activation. IFNγ-producing mast cells were closely aligned with the recruitment of CD8+ T cells in the early phase of vitiligo skin. sSCF released by KCs through stress-enhanced MMP9-dependent proteolytic cleavage recruited mast cells into sites of inflamed skin (Perilesion vs. lesion, 13.00 ± 4.00/HPF vs. 26.60 ± 5.72/HPF, P <0.05). Moreover, IFNγ-producing mast cells were also observed in mouse tail skin following challenge with Tyrp-2 180 (0 h vs. 48 h post-recall, 0.00 ± 0.00/HPF vs. 3.80 ± 1.92/HPF, P <0.05). The IFNγ+ mast cell and CD8+ T cell counts were lower in the skin of MrgB2-/-mice than in those of wild-type mice (WT vs. KO 48 h post-recall, 4.20 ± 0.84/HPF vs. 0.80 ± 0.84/HPF, P <0.05). Mast cells activated by MrgX2 serve as a local IFNγ producer that bridges between innate and adaptive immune responses against MCs in early vitiligo. Targeting MrgX2-mediated mast cell activation may represent a new strategy for treating vitiligo.

No signs of mast cell involvement in long-COVID: Acase-control study.

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients.

TRPV1 and mast cell involvement in repeated variate stress-induced urinary bladder dysfunction in adult female mice.

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1+ nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased (P ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. Trpv1 knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg-Kitw-sh) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction.NEW & NOTEWORTHY Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

Investigating the overlapping presentation of irritable bowel syndrome and vulvodynia: a scoping review of the evidence and mechanisms.

Vulvodynia is a complex and multifactorial medical condition characterized by pain in the vulvar area without any identifiable cause. Vulvodynia is underdiagnosed, leading to increased risk of sexual dysfunction and reduced quality of life. Irritable bowel syndrome (IBS) is a gastrointestinal disorder predominantly affecting women. Vulvodynia and IBS frequently co-occur in women, with a 2- to 4-fold increased likelihood of IBS diagnosis in those with vulvodynia. These conditions may share underlying causes, highlighting the need for research to better understand their shared pathophysiology and develop effective therapeutics. The aim of this scoping review was to assess the evidence of simultaneous presentation of IBS and vulvodynia. A comprehensive search was conducted in 6 databases between inception of database and August 2023: PubMed, Web of Science, Scopus, Science Direct, Google Scholar, and Cochrane Library. Studies included primary research about IBS and vulvodynia in terms of presentation overlap, diagnosis, or treatment. Data were extracted from eligible studies, summarized, and collated. Of the 306 unique articles identified, 33 were included in the final analysis: 20 cross-sectional studies, 4 case-control studies, 2 case reports, 4 cohort studies, 2 quasi-experimental studies, and 1 randomized trial. Common themes included a high prevalence of overlapping vulvodynia and IBS with a significant diagnostic delay in vulvodynia, mast cell involvement and visceral hypersensitization as common pathophysiology, and the need for a multimodal treatment. Our review adds to the evidence that there is an association between vulvodynia and IBS. Despite this, research on the underlying molecular mechanisms of this association is scarce, and diagnostic delays persist for vulvodynia. Increasing awareness of the overlap of these conditions will improve screening for vulvodynia in the patient population with IBS, thereby improving the diagnostic delay, and understanding the pathophysiology will enable treatment strategies that address both conditions.

Involvement of Mast Cells in the Pathology of COVID-19: Clinical and Laboratory Parallels.

Recent studies suggested the potential role of mast cells (MCs) in the pathology of coronavirus disease 2019 (COVID-19). However, the precise description of the MCs' activation and the engagement of their proteases is still missing. The objective of this study was to further reveal the importance of MCs and their proteases (chymase, tryptase, and carboxypeptidase A3 (CPA3)) in the development of lung damage in patients with COVID-19. This study included 55 patients who died from COVID-19 and 30 controls who died from external causes. A histological analysis of the lung parenchyma was carried out to assess the protease profiles and degranulation activity of MCs. In addition, we have analyzed the general blood test, coagulogram, and C-reactive protein. The content of tryptase-positive MCs (Try-MCs) in the lungs of patients with COVID-19 was higher than in controls, but their degranulation activity was lower. The indicators of chymase-positive MCs (Chy-MCs) were significantly lower than in the controls, while the content of CPA3-positive MCs (CPA3-MCs) and their degranulation activity were higher in patients with COVID-19. In addition, we have demonstrated the existence of correlations (positive/negative) between the content of Try-MCs, Chy-MCs, and CPA3-MCs at different states of their degranulation and presence (co-adjacent/single) and the levels of various immune cells (neutrophils, eosinophils, basophils, and monocytes) and other important markers (blood hemoglobin, activated partial thromboplastin time (aPTT), international normalized ratio (INR), and fibrinogen). Thus, the identified patterns suggest the numerous and diverse mechanisms of the participation of MCs and their proteases in the pathogenesis of COVID-19, and their impact on the inflammatory process and coagulation status. At the same time, the issue requires further study in larger cohorts of patients, which will open up the possibility of using drugs acting on this link of pathogenesis to treat lung damage in patients with COVID-19.

The Prostaglandin D2 Receptor CRTH2 Contributes to Airway Hyperresponsiveness during Airway Inflammation Induced by Sensitization without an Adjuvant in Mice

Introduction: Prostaglandin D2 (PGD2), which is produced mainly by Th2 cells and mast cells, promotes a type-2 immune response by activating Th2 cells, mast cells, eosinophils, and group 2 innate lymphoid cells (ILC2s) via its receptor, chemoattractant receptor-homologous molecules on Th2 cells (CRTH2). However, the role of CRTH2 in models of airway inflammation induced by sensitization without adjuvants, in which both IgE and mast cells may play major roles, remain unclear. Methods: Wild-type (WT) and CRTH2-knockout (KO) mice were sensitized with ovalbumin (OVA) without an adjuvant and then challenged intranasally with OVA. Airway inflammation was assessed based on airway hyperresponsiveness (AHR), lung histology, number of leukocytes, and levels of type-2 cytokines in the bronchoalveolar lavage fluid (BALF). Results: AHR was significantly reduced after OVA challenge in CRTH2 KO mice compared to WT mice. The number of eosinophils, levels of type-2 cytokines (IL-4, IL-5, and IL-13) in BALF, and IgE concentration in serum were decreased in CRTH2 KO mice compared to WT mice. However, lung histological changes were comparable between WT and CRTH2 KO mice. Conclusion: CRTH2 is responsible for the development of asthma responses in a mouse model of airway inflammation that features prominent involvement of both IgE and mast cells.

A highly selective KIT inhibitor MOD000001 suppresses IgE-mediated mast cell activation

BackgroundThe KIT receptor tyrosine kinase and its ligand, stem cell factor (SCF) control proliferation and survival of mast cells. Thus, targeting KIT signaling may show promise for the treatment of allergic diseases involving mast cells. Recently, we discovered a new compound MOD000001 as a potential small-molecule KIT kinase inhibitor by using an in silico approach. ObjectiveThis study determined whether MOD000001 is highly-selective to KIT, inhibits KIT signaling in mast cells, and affects IgE-mediated mast cell activation. MethodsThe interaction of MOD000001 with 468 human kinases and its inhibitory activity against KIT were profiled and evaluated by using KinomeScan and cell-free kinase assays, respectively. The effects of MOD000001 on SCF-dependent signaling were examined by using primary mouse and human mast cells. The effects of MOD000001 on SCF-induced degranulation and passive cutaneous anaphylactic (PCA) reaction were examined in mice. ResultsMOD000001 interacted with KIT and inhibited KIT kinase activity with high selectivity. MOD000001 suppressed SCF-induced KIT signaling in mouse and human mast cells and in mice. PCA reaction was suppressed in mice treated with MOD000001 both for a short-term (1 week) and a long-term (7 weeks). Mice treated with MOD000001 for a long-term, but not for a short-term, showed skin mast cell reduction. ConclusionsMOD000001 is a highly selective KIT inhibitor that can suppress IgE-mediated mast cell activation in vivo. MOD000001 may do so by reducing tissue mast cell numbers or by other unknown mechanisms. The findings suggest potential benefits of MOD000001 for allergic diseases involving IgE-mediated mast cell activation.

An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation.

Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults. This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain. Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling. By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

The effect of myeloablative radiation on urinary bladder mast cells

Radiation-induced cystitis is an inflammatory condition affecting the urinary bladder, which can develop as a side effect of abdominopelvic radiotherapy, specifically external-beam radiation therapy or myeloablative radiotherapy. A possible involvement of mast cells in the pathophysiology of radiation-induced cystitis has been indicated in cases of external-beam radiation therapy; however, there is no evidence that these findings apply to the myeloablative aetiology. As such, this study investigated potential changes to urinary bladder mast cell prevalence when exposed to myeloablative radiation. Lethally irradiated C57BL/6J mice that received donor rescue bone marrow cells exhibited an increased mast cell frequency amongst host leukocytes 1 week following irradiation. By 4 weeks, no significant difference in either frequency or cell density was observed. However mast cell diameter was smaller, and a significant increase in mast cell number in the adventitia was observed. This study highlights that mast cells constitute a significant portion of the remaining host leukocyte population following radiation exposure, with changes to mast cell distribution and decreased cell diameter four weeks following radiation-induced injury.

Role of mechanical stimulus in mast cell activation

ABSTRACT Mast cells play a critical role in allergic reactions and other types of inflammatory diseases. There is circumstantial evidence from preclinical approaches that suggest the involvement of mast cells in the development of various diseases. However, the mediator of mast cell accumulation and proliferation in these diseases remains unknown. Studies of mast cell activation have primarily focused on IgE-mediated mast cell-dependent anaphylaxis. Recently, several studies implied the link between mast cell activation and mechanical stimulus. On the surface, mast cells express several mechanoreceptors, such as TRPV2 and ADGRE2, to access external mechanical force. Mechanosensitive cells, including neurons and epithelial cells, secrete inflammatory cytokines to activate mast cells when countering scratching or trauma. Integrin-mediated pathways that sense mechanical properties will migrate mast cells to areas with stiffness variations. In this review, we discuss the evidence linking mechanical stimulus to mast cell activation.

Pediatric tuina treatment for spleen deficiency diarrhea regulated through the skin-brain-gut axis and mast cell degranulation

BackgroundPediatric tuina is an effective alternative therapy for managing spleen deficiency diarrhea. The application of spleen-meridian and large-intestine-meridian points has been shown to alleviate symptoms and has garnered some support from evidence-based medicine. Nonetheless, there remains a dearth of research elucidating the biological effects of these specific acupoints. This study aimed to explore their effects by focusing on the material basis involving mast cells (MCs). MethodsThe experimental design induced spleen-deficiency diarrhea in Kunming mice through a 7-day administration of Rheum officinale extract through gavage. Following this induction, treatment was initiated, employing a combination of spleen-meridian and large-intestine-meridian points over 6 days. Efficacy was assessed using fecal scoring. Colonic structure was assessed through hematoxylin-eosin staining, while toluidine blue staining was employed to observe MC degranulation within the skin-brain-gut axis. Immunohistochemistry was performed to detect tryptase release from MCs. ResultsThe treatment combining spleen-meridian and large-intestine-meridian points markedly ameliorated diarrhea symptoms and improved fecal scores in Kunming mice exhibiting spleen deficiency. Pediatric tuina treatment facilitated the restoration of the colonic barrier and reduction in MC counts within the skin acupoint-brain-gut axis, consequently affecting the biologically active substance tryptase. ConclusionThis study reveals the biological mechanism underlying the efficacy of specific acupoints in pediatric tuina, employing a holistic perspective encompassing the skin-brain-gut axis and MCs. Our findings substantiate the scientific basis for the effectiveness of tuina therapy in managing diarrhea and offer a new avenue for fundamental research on specific acupoints within pediatric tuina.

Machine learning–based identification and characterization of mast cells in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis. ObjectiveUsing machine learning, we localized and characterized esophageal mast cells to decipher their potential role in disease pathology. MethodsEsophageal biopsy samples (EoE, control) were stained for mast cells by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize mast cells, designated Mast Cell-Artificial Intelligence (MC-AI). ResultsMC-AI enumerated cell counts with high accuracy. During active EoE, epithelial mast cells increased and lamina propria (LP) mast cells decreased. In controls and EoE remission patients, papillae had the highest mast cell density and negatively correlated with epithelial mast cell density. Mast cell density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater mast cell degranulation in the epithelium, papillae, and LP in EoE patients compared with control individuals. Mast cells were localized further from the basement membrane in active EoE than EoE remission and control individuals but were closer than eosinophils to the basement membrane in active EoE. ConclusionUsing MC-AI, we identified a distinct population of homeostatic esophageal papillae mast cells; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial mast cell levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of mast cells in EoE and other disorders.

Involvement of peripheral mast cells in a fibromyalgia model in mice

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5–4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80–90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.

Mast Cells in Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is a syndrome of high type 2 inflammation and is known to critically involve mast cell activation. The mast cell is an important cell in the baseline inflammatory processes in the upper and lower airway by maintaining and amplifying type 2 inflammation. But it also is prominent in the hypersensitivity reaction to COX-1 inhibition which defines this condition. Recent work highlights the mast cell as a focal point in AERD pathogenesis. Using AERD as a specific model of both high type 2 asthma and chronic sinusitis, the role of mast cell activity can be better understood in other aspects of airway inflammation. Further dissecting out the mechanism of COX-1-mediated mast cell activation in AERD will be an important next phase in our understanding of NSAID-induced hypersensitivity as well as AERD pathophysiology.

Development and evaluation of mouse anti-Ara h 1 and Ara h 3 IgE monoclonal antibodies for advancing peanut allergy research

Immediate hypersensitivity reactions to peanuts are a considerable public health concern due to the acute and severe IgE mediated reactions. To conduct research on the pathogenesis and therapeutics of peanut allergies, it is imperative to have mouse anti-crude peanut extract (CPE) IgE monoclonal antibodies (mAbs) for both in-vitro and in-vivo assays. Without these tools, it is difficult to advance research in this field.In this study, four hybridomas producing anti-CPE IgE mAbs were developed and the IgE mAbs were validated using immune-blot analysis, Sandwich ELISA, Indirect ELISA, a cell-based assay using RBL-2H3 cells, and footpad type I hypersensitivity reaction studies in mice.The results indicate that two of the four mAbs can be effectively used for both in-vitro and in-vivo peanut allergy studies, as they induce allergic reactions with sensitization alone in mice. These novel anti-Ara h1 and Ara h 3 IgE mAbs, in combination with the detailed protocols outlined in this article, offer valuable guidance for studying acute allergic reactions involving mast cells across various platforms. With some considerations, the IgE mAbs can significantly advance peanut allergy research.

Tryptase-Positive Mast Cells Promote Adipose Fibrosis in Secondary Lymphedema through PDGF.

Lymphedema is a chronic and progressive condition that causes physical disfigurement and psychological trauma due to the accumulation of lymphatic fluid in the interstitial space. Once it develops, lymphedema is difficult to treat because it leads to the fibrosis of adipose tissue. However, the mechanism behind this remains unclear. The purpose of this study was to investigate the involvement of mast cells (MCs) in the adipose tissues of patients with lymphedema. We found that fibrosis spread through blood vessels in the adipose tissues of lymphedema patients, and the expression of the collagen I and III genes was significantly increased compared to that of those in normal adipose tissue. Immunostaining of vimentin and α-smooth muscle actin showed that fibroblasts were the main cellular components in severely fibrotic regions. Toluidine blue staining confirmed a significant increase in the number of MCs in the adipose tissues of lymphedema patients, and immunostaining of serial sections of adipose tissue showed a significant increase in the number of tryptase-positive cells in lymphedema tissues compared with those in normal adipose tissues. Linear regression analyses revealed significant positive correlations between tryptase and the expressions of the TNF-α, platelet-derived growth factor (PDGF)-A, and PDGFR-α genes. PDGF-A-positive staining was observed in both fibroblasts and granules of tryptase-positive MCs. These results suggest that MC-derived tryptase plays a role in the fibrosis of adipose tissue due to lymphedema directly or in cooperation with other mediators.

Dermal Exposure to Vesicating Nettle Agent Phosgene Oxime: Clinically Relevant Biomarkers and Skin Injury Progression in Murine Models.

Phosgene oxime (CX), categorized as a vesicating chemical threat agent, causes effects that resemble an urticant or nettle agent. CX is an emerging potential threat agent that can be deployed alone or with other chemical threat agents to enhance their toxic effects. Studies on CX-induced skin toxicity, injury progression, and related biomarkers are largely unknown. To study the physiologic changes, skin clinical lesions and their progression, skin exposure of SKH-1 and C57BL/6 mice was carried out with vapor from 10 μl CX for 0.5-minute or 1.0-minute durations using a designed exposure system for consistent CX vapor exposure. One-minute exposure caused sharp (SKH-1) or sustained (C57BL/6) decrease in respiratory and heart rate, leading to mortality in both mouse strains. Both exposures caused immediate blanching, erythema with erythematous ring (wheel) and edema, and an increase in skin bifold thickness. Necrosis was also observed in the 0.5-minute CX exposure group. Both mouse strains showed comparative skin clinical lesions upon CX exposure; however, skin bifold thickness and erythema remained elevated up to 14 days postexposure in SKH-1 mice but not in C57BL/6 mice. Our data suggest that CX causes immediate changes in the physiologic parameters and gross skin lesions resembling urticaria, which could involve mast cell activation and intense systemic toxicity. This novel study recorded and compared the progression of skin injury to establish clinical biomarkers of CX dermal exposure in both the sexes of two murine strains relevant for skin and systemic injury studies and therapeutic target identification. SIGNIFICANCE STATEMENT: Phosgene oxime (CX), categorized as a vesicating agent, is considered as a potent chemical weapon and is of high military and terrorist threat interest since it produces rapid onset of severe injury as an urticant. However, biomarkers of clinical relevance related to its toxicity and injury progression are not studied. Data from this study provide useful clinical markers of CX skin toxicity in mouse models using a reliable CX exposure system for future mechanistic and efficacy studies.

What initiates chemical intolerance? Findings from a large population-based survey of U.S. adults

BackgroundWorldwide observations point to a two-stage theory of disease called Toxicant-Induced Loss of Tolerance (TILT): Stage I, Initiation by an acute high-level or repeated lower-level chemical exposures, followed by Stage II, Triggering of multisystem symptoms by previously tolerated, structurally diverse chemical inhalants, foods/food additives and drugs. Until recently, there was no known biological mechanism that could explain these observations. In 2021, we published a plausible and researchable two-stage biomechanism for TILT involving mast cells: Stage I, Initiation via mast cell sensitization; Stage II, Triggering of mast cell degranulation by previously tolerated exposures, resulting in the release of thousands of mediators, including histamine and a host of inflammatory molecules. The objective of this study was to identify common TILT initiators.MethodsA randomized, population-based sample of 10,981 U.S. adults responded to a survey which included items concerning medical diagnoses, personal exposures, antibiotic use, and several possible initiators of Chemical Intolerance (CI). CI was assessed using the internationally validated Quick Environmental Exposure and Sensitivity Inventory (QEESI). Participants identified as chemically intolerant were asked to recall when their intolerances began and what they felt had initiated their condition.ResultsTwenty percent met QEESI criteria for TILT, approximately half of whom identified one or more initiating exposures. Initiators in order of frequency were mold (15.6%), pesticides (11.5%), remodeling/new construction (10.7%), medical/surgical procedures (11.3%), fires/combustion products (6.4%), and implants (1.6%). Protracted antibiotic use for infections involving the prostate, skin, tonsils, gastrointestinal tract, and sinuses were strongly associated with TILT/CI (OR > 2).DiscussionParticipants identified two broad classes of TILT initiators: 1) fossil fuel-derived toxicants (i.e., from coal, oil, natural gas), their combustion products, and/or synthetic organic chemical derivatives, e.g., pesticides, implants, drugs/antibiotics, volatile organic compounds (VOCs); and 2) biogenic toxicants, e.g., particles and VOCs from mold or algal blooms. One in four primary care patients suffers from Medically Unexplained Symptoms (MUS). Doctors in primary care, neurology, psychiatry, psychology, occupational medicine, and allergy/immunology would be well-advised to include TILT in their differential diagnosis of patients with so-called MUS. Because 20% of U.S. adults meet QEESI criteria for CI, the role of contemporary exposures in initiating and exacerbating these conditions via mast cells needs our immediate attention. There is a concomitant need for policies and practices that reduce initiating exposures as well as ubiquitous and often unavoidable triggers such as fragranced personal care, cleaning, and laundry products in multi-occupant housing, workplaces, medical settings, schools, places of worship, and all public buildings—literally anywhere air is shared. Fossil fuels are assaulting humans and other animal species both from within via mast cell sensitization, and from without via climate change.

Mast Cell Involvement in the Pathogenesis of Selected Musculoskeletal Diseases.

In recent years, there has been a noteworthy revival of interest in the function of mast cells (MCs) in the human body. It is now acknowledged that MCs impact a wide array of processes beyond just allergies, leading to a shift in research direction. Unfortunately, some earlier conclusions were drawn from animal models with flawed designs, particularly centered around the receptor tyrosine kinase (Kit) pathway. Consequently, several subsequent findings may have been unreliable. Thus, what is now required is a re-examination of these earlier findings. Nevertheless, the remaining data are fascinating and hold promise for a better comprehension of numerous diseases and the development of more effective therapies. As the field continues to progress, many intriguing issues warrant further investigation and analysis. For instance, exploring the bidirectional action of MCs in rheumatoid arthritis, understanding the extent of MCs' impact on symptoms associated with Ehlers-Danlos syndrome, and unraveling the exact role of the myofibroblast-mast cell-neuropeptides axis in the joint capsule during post-traumatic contractures are all captivating areas for exploration. Hence, in this review, we summarize current knowledge regarding the influence of MCs on the pathogenesis of selected musculoskeletal diseases, including rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, gout, muscle and joint injuries, tendinopathy, heterotopic ossification, and Ehlers-Danlos syndrome. We believe that this review will provide in-depth information that can guide and inspire further research in this area.

Secretory leukocyte protease inhibitor modulates FcεRI-dependent but not Mrgprb2-dependent mastocyte function in psoriasis

Psoriasis, which involves mast cells, is a chronic inflammatory skin disorder whose pathophysiology is still not fully understood. We investigated the role of secretory leukocyte protease inhibitor (SLPI), a potential inhibitor of mastocyte serine proteases, on mast cell-dependent processes of relevance to the skin barrier defense in psoriasis. Here, we demonstrate that the dermal mast cells of patients with psoriasis express SLPI but not those of healthy donors. Moreover, SLPI transcripts were found to be markedly upregulated in murine mast cells by mediators derived from psoriasis skin explant cultures. Using mast cells from SLPI-deficient mice and their SLPI+ wild-type controls, we show that SLPI inhibits the activity of serine protease chymase in mastocytes. SLPI was also found to enhance the degranulation of mast cells activated via anti-IgE Abs but not Mrgprb2 ligands. Finally, we demonstrate that the expression and function of Mrgprb2 in mast cells are suppressed by a normal and, to a larger extent, psoriatic skin environment. Together, these findings reveal mechanisms underlying FcεRI– and Mrgprb2-dependent mast cell function that have not been described previously.