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1.
Front Immunol ; 13: 879754, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711438

RESUMO

Chronic spontaneous urticaria (CSU) is defined as recurrent episodes of spontaneous wheal development and/or angioedema for more than six weeks and at least twice a week. The core link in the pathogenesis of CSU is the activation of mast cells, T cells, eosinophils, and other immune cells infiltrating around the small venules of the lesion. Increased vascular permeability, vasodilatation, and recruitment of inflammatory cells directly depend on mast cell mediators' release. Complex regulatory systems tightly influence the critical roles of mast cells in the local microenvironment. The bias toward Th2 inflammation and autoantibodies derived from B cells, histamine expressed by basophils, and initiation of the extrinsic coagulation pathway by eosinophils or monocytes exerts powerful modulatory influences on mast cells. Cell-to-cell interactions between mast cells and eosinophils/T cells also are regulators of their function and may involve CSU's pathomechanism. This review summarizes up-to-date knowledge regarding the crosstalk between mast cells and other immune cells, providing the impetus to develop new research concepts and treatment strategies for CSU.


Assuntos
Urticária Crônica , Urticária , Basófilos/metabolismo , Histamina/metabolismo , Humanos , Mastócitos
2.
Front Immunol ; 13: 880412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35711458

RESUMO

IgE-mediated release of proinflammatory mediators and cytokines from basophils and mast cells is a central event in allergic disorders. Several groups of investigators have demonstrated the presence of autoantibodies against IgE and/or FcεRI in patients with chronic spontaneous urticaria. By contrast, the prevalence and functional activity of anti-IgE autoantibodies in atopic dermatitis (AD) are largely unknown. We evaluated the ability of IgG anti-IgE from patients with AD to induce the in vitro IgE-dependent activation of human basophils and skin and lung mast cells. Different preparations of IgG anti-IgE purified from patients with AD and rabbit IgG anti-IgE were compared for their triggering effects on the in vitro release of histamine and type 2 cytokines (IL-4, IL-13) from basophils and of histamine and lipid mediators (prostaglandin D2 and cysteinyl leukotriene C4) from human skin and lung mast cells. One preparation of human IgG anti-IgE out of six patients with AD induced histamine release from basophils, skin and lung mast cells. This preparation of human IgG anti-IgE induced the secretion of cytokines and eicosanoids from basophils and mast cells, respectively. Human monoclonal IgE was a competitive antagonist of both human and rabbit IgG anti-IgE. Human anti-IgE was more potent than rabbit anti-IgE for IL-4 and IL-13 production by basophils and histamine, prostaglandin D2 and leukotriene C4 release from mast cells. Functional anti-IgE autoantibodies rarely occur in patients with AD. When present, they induce the release of proinflammatory mediators and cytokines from basophils and mast cells, thereby possibly contributing to sustained IgE-dependent inflammation in at least a subset of patients with this disorder.


Assuntos
Basófilos , Dermatite Atópica , Animais , Autoanticorpos/farmacologia , Citocinas/farmacologia , Eicosanoides , Histamina , Humanos , Imunoglobulina E , Imunoglobulina G/farmacologia , Interleucina-13/farmacologia , Interleucina-4/farmacologia , Leucotrieno C4 , Mastócitos , Prostaglandinas , Coelhos
3.
Front Immunol ; 13: 902494, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693800

RESUMO

Basophils are the rarest granulocytes and have long been overlooked in immunological research due to their rarity and similarities with tissue-resident mast cells. In the last two decades, non-redundant functions of basophils have been clarified or implicated in a broad spectrum of immune responses, particularly by virtue of the development of novel analytical tools for basophils. Basophils infiltrate inflamed tissues of patients with various disorders, even though they circulate in the bloodstream under homeostatic conditions. Depletion of basophils results in the amelioration or exaggeration of inflammation, depending on models of disease, indicating basophils can play either beneficial or deleterious roles in a context-dependent manner. In this review, we summarize the recent findings of basophil pathophysiology under various conditions in mice and humans, including allergy, autoimmunity, tumors, tissue repair, fibrosis, and COVID-19. Further mechanistic studies on basophil biology could lead to the identification of novel biomarkers or therapeutic targets in a broad range of diseases.


Assuntos
COVID-19 , Hipersensibilidade , Animais , Basófilos , Humanos , Inflamação , Mastócitos/patologia , Camundongos
4.
Front Immunol ; 13: 861545, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35669782

RESUMO

Cutaneous melanoma is one of the most aggressive human malignancies and shows increasing incidence. Mast cells (MCs), long-lived tissue-resident cells that are particularly abundant in human skin where they regulate both innate and adaptive immunity, are associated with melanoma stroma (MAMCs). Thus, MAMCs could impact melanoma development, progression, and metastasis by secreting proteases, pro-angiogenic factors, and both pro-inflammatory and immuno-inhibitory mediators. To interrogate the as-yet poorly characterized role of human MAMCs, we have purified MCs from melanoma skin biopsies and performed RNA-seq analysis. Here, we demonstrate that MAMCs display a unique transcriptome signature defined by the downregulation of the FcεRI signaling pathway, a distinct expression pattern of proteases and pro-angiogenic factors, and a profound upregulation of complement component C3. Furthermore, in melanoma tissue, we observe a significantly increased number of C3+ MCs in stage IV melanoma. Moreover, in patients, C3 expression significantly correlates with the MC-specific marker TPSAB1, and the high expression of both markers is linked with poorer melanoma survival. In vitro, we show that melanoma cell supernatants and tumor microenvironment (TME) mediators such as TGF-ß, IL-33, and IL-1ß induce some of the changes found in MAMCs and significantly modulate C3 expression and activity in MCs. Taken together, these data suggest that melanoma-secreted cytokines such as TGF-ß and IL-1ß contribute to the melanoma microenvironment by upregulating C3 expression in MAMCs, thus inducing an MC phenotype switch that negatively impacts melanoma prognosis.


Assuntos
Melanoma , Neoplasias Cutâneas , Complemento C3/metabolismo , Humanos , Mastócitos , Melanoma/patologia , Peptídeo Hidrolases/metabolismo , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/genética , Regulação para Cima
5.
Bioengineered ; 13(5): 13752-13766, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35746853

RESUMO

When mosquitoes probe to feed blood, they inoculate a mixture of salivary molecules into vertebrate hosts' skin causing acute inflammatory reactions where mast cell-derived mediators are involved. Mosquito saliva contains many proteins with largely unknown biological functions. Here, two Aedes albopictus salivary proteins - adenosine deaminase (alADA) and al34k2 - were investigated for their immunological impact on mast cells and two mast cell-specific proteases, the tryptase and the chymase. Mouse bone marrow-derived mast cells were challenged with increased concentrations of recombinant alADA or al34k2 for 1, 3, and 6 h, and to measure mast cell activation, the activity levels of ß-hexosaminidase and tryptase and secretion of IL-6 were evaluated. In addition, a direct interaction between alADA or al34k2 with tryptase or chymase was investigated. Results show that bone marrow-derived mast cells challenged with 10 µg/ml of alADA secreted significant levels of ß-hexosaminidase, tryptase, and IL-6. Furthermore, both al34k2 and alADA are cut by human tryptase and chymase. Interestingly, al34k2 dose-dependently enhance enzymatic activity of both tryptase and chymase. In contrast, while alADA enhances the enzymatic activity of tryptase, chymase activity was inhibited. Our finding suggests that alADA and al34k2 via interaction with mast cell-specific proteases tryptase and chymase modulate mast cell-driven immune response in the local skin microenvironment. alADA- and al34k2-mediated modulation of tryptase and chymase may also recruit more inflammatory cells and induce vascular leakage, which may contribute to the inflammatory responses at the mosquito bite site.


Assuntos
Aedes , Mastócitos , Adenosina Desaminase , Aedes/metabolismo , Animais , Quimases/metabolismo , Endopeptidases , Humanos , Interleucina-6 , Mastócitos/metabolismo , Camundongos , Peptídeo Hidrolases , Proteínas e Peptídeos Salivares , Triptases/metabolismo , beta-N-Acetil-Hexosaminidases
6.
BMC Womens Health ; 22(1): 253, 2022 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-35752827

RESUMO

BACKGROUND: The diagnosis of endometriosis (EMs) is still based on laparoscopic observation. This study tries to verify whether exosomal tRNA-derived fragments (tRFs) in leucorrhea can be used as non-invasive diagnostic markers. METHODS: Endometrial tissues and leucorrhea were sampled from women hospitalized in Ningbo University Affiliated Hospital from January 2021 to July 2021 with (n = 26) and without endometriosis (n = 25). Exosomes were isolated from samples by differential centrifugation. The small RNA sequencing was performed to detect the exosomal tRNA halves (tiRNAs)&tRFs. RNA probe and immunofluorescence antibody were used to localize the origin of tRFs. From mast cell lines infected with tRF-Leu-AAG-001 siRNA, we observed the change in vascular capacity and expression of inflammatory factors. The specificity and sensitivity tRF were determined by receiver operating characteristic analyses. RESULTS: 63 up-regulated and 45 down-regulated tRFs&tiRNAs were identified in ectopic exosomes. We selected tRF-Leu-AAG-001 as a candidate marker through KEGG pathway enrichment and PCR verification. We found that mast cells highly expressed tRF-Leu-AAG-001 in ectopic foci by immunofluorescence staining. We used siRNA to silenced tRF-Leu-AAG-001 expression in luva, qPCR analysis showed IL-6, IL-10, IL-1ß, and TNF-α were significantly decreased. Meanwhile, tRF-Leu-AAG-001 siRNA dramatically reduced the angiogenic ability of luva. Finally, we examined the expression of exosomal tRF-Leu-AAG-001 in the leucorrhea. It was found exosomal tRF-Leu-AAG-001 had high specificity and sensitivity for predicting the occurrence of ectopic disease. CONCLUSIONS: Exosomal tRF-Leu-AAG-001 derived from mast cells in ectopic foci might promote inflammation and angiogenesis. Meanwhile, leucorrhea exosomal tRF-Leu-AAG-001 could be a potential diagnostic biomarker for endometriosis.


Assuntos
Endometriose , Exossomos , Endometriose/genética , Exossomos/genética , Exossomos/metabolismo , Feminino , Humanos , Mastócitos/metabolismo , RNA Interferente Pequeno/metabolismo , RNA de Transferência/genética , RNA de Transferência/metabolismo
7.
J Immunol Res ; 2022: 6833867, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35755168

RESUMO

Purpose: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disorder. Although ferroptosis is closely associated with inflammation, oxidative stress, and neuropathic pain, its role in CP/CPPS has not yet been elucidated. Therefore, we sought to explore the role and mechanism of ferroptosis in the prostatitis development. Methods: The experimental autoimmune prostatitis (EAP) was established through intradermal immunization of prostate extract. Iron chelator deferoxamine (DFO) and free radical scavenger edaravone (EDA) were applied to evaluate the effects of ferroptosis inhibition on oxidative stress, ferroptosis, inflammation, fibrosis, and mast cell activation in the context of CP/CPPS. Results: Increased generation of lipid peroxidation products (ROS and MDA) and decreased activities of antioxidant enzymes (SOD and CAT) suggested an aberrant oxidative stress status in EAP model. Elevated iron concentration was observed in the EAP model. Meanwhile, we discovered significant biological performances associated with ferroptosis in CP/CPPS, including the downregulation of the system Xc-/GPX4 axis and the upregulation of the ACSL4/LPCAT3 axis. EAP rats performed serious leukocyte infiltration, advanced inflammatory grade, and abnormal expression of inflammatory mediators. Abundant collagen deposition, enhanced RhoA, ROCK1, and α-SMA protein levels indicated that EAP rats were prone to suffer from stromal fibrosis compared with control group. An elevated number of degranulated mast cells and corresponding marker TPSB2 represented that mast cell-sensitized pain was amplified in the EAP model. Furthermore, reduction of NRF2/HO-1 indicated a vulnerability of EAP towards ferroptosis response. However, application of DFO and EDA had partially reversed the adverse influences mentioned above. Conclusion: We first demonstrated that ferroptosis might be a crucial factor of chronic prostatitis progression. Inhibition of ferroptosis using DFO and EDA represented a promising approach for treating prostatitis by ameliorating inflammation, fibrosis, and mast cell activation.


Assuntos
Doenças Autoimunes , Dor Crônica , Ferroptose , Prostatite , Animais , Doença Crônica , Dor Crônica/complicações , Dor Crônica/metabolismo , Modelos Animais de Doenças , Fibrose , Humanos , Inflamação/metabolismo , Masculino , Mastócitos/metabolismo , Dor Pélvica/complicações , Dor Pélvica/metabolismo , Prostatite/complicações , Prostatite/tratamento farmacológico , Ratos , Quinases Associadas a rho/metabolismo
8.
Chin J Nat Med ; 20(6): 421-431, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35750382

RESUMO

Pseudo-allergic reactions (PARs) widely occur upon application of drugs or functional foods. Anti-pseudo-allergic ingredients from natural products have attracted much attention. This study aimed to investigate anti-pseudo-allergic compounds in licorice. The anti-pseudo-allergic effect of licorice extract was evaluated in rat basophilic leukemia 2H3 (RBL-2H3) cells. Anti-pseudo-allergic compounds were screened by using RBL-2H3 cell extraction and the effects of target components were verified further in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs) and mice. Molecular docking and human MRGPRX2-expressing HEK293T cells (MRGPRX2-HEK293T cells) extraction were performed to determine the potential ligands of MAS-related G protein-coupled receptor-X2 (MRGPRX2), a pivotal target for PARs. Glycyrrhizic acid (GA) and licorice chalcone A (LA) were screened and shown to inhibit Compound48/80-induced degranulation and calcium influx in RBL-2H3 cells. GA and LA also inhibited degranulation in MPMCs and increase of histamine and TNF-α in mice. LA could bind to MRGPRX2, as determined by molecular docking and MRGPRX2-HEK293T cell extraction. Our study provides a strong rationale for using GA and LA as novel treatment options for PARs. LA is a potential ligand of MRGPRX2.


Assuntos
Antialérgicos , Glycyrrhiza , Hipersensibilidade , Animais , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Cálcio/metabolismo , Degranulação Celular , Células HEK293 , Humanos , Hipersensibilidade/tratamento farmacológico , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/metabolismo , Ratos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Receptores de Neuropeptídeos/uso terapêutico
9.
Zhongguo Fei Ai Za Zhi ; 25(6): 385-395, 2022 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-35747917

RESUMO

BACKGROUND: Reticulosome family gene 1 (RTN1) is a reticulosome-encoding gene associated with the endoplasmic reticulum. RTN1 plays a key role in membrane trafficking or neuroendocrine secretion of neuroendocrine cells, while RTN1 serves as a potential diagnostic/therapeutic marker for neurological diseases and cancer. However, the expression of RTN1 and its effect on the immune microenvironment in patients with lung adenocarcinoma have not been reported. In this study, we aimed to investigate the expression of RTN1 in lung adenocarcinoma and its correlation with immune infiltration and survival in lung adenocarcinoma using public databases and bioinformatics network tools. METHODS: Expression levels of RTN1 mRNA in tumor and normal tissues were analyzed using Tumor Immune Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). RTN1 protein expression was examined using the Human Protein Atlas. The clinical prognostic significance of RTN1 was analyzed using the GEPIA2 plotter database. To further confirm the potential function of RTN1, the data were analyzed using gene set enrichment analysis. In addition, We performed dimensionality-reduced clustering analysis at the single-cell sequencing level on two datasets from the Tumor Immune Single-cell Hub (TISCH) database to observe the cellular clustering of RTN1 in different types of immune cells. Using the TIMER online tool to analyze and predict the infiltration abundance of different types of immune cells in the immune microenvironment of lung adenocarcinoma patients in the TCGA cohort; TIMER and CIBERSORT were used to study the relationship between genes co-expressed with RTN1 and its associated tumor-infiltrating immune cells; finally, TIMER was used to analyze the relationship between RTN1 and immune correlations between immune checkpoints. RESULTS: We found that RTN1 expression was decreased in patients with lung adenocarcinoma and was closely related to patient prognosis. RTN1 is involved in the process of phagosome formation, hematopoietic cell formation and cell adhesion, and plays an important role in T cell activation. Using cBioPortal and TCGA data to analyze, it is found that RTN1 is significantly associated with BTK, CD4, ECSF1R, MNDA, NCKAP1L and SNX20. High expression of the above genes may cause significant upregulation of CD4+ T cells, mast cells, monocytes, myeloid dendritic cells and M1 macrophages. The expression of RTN1 is closely related to the common immune checkpoints CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, TIGIT and SIGLEC15 immune checkpoints. CONCLUSIONS: RTN1 may act as a tumor suppressor gene and indicate better prognosis. Furthermore, RTN1 is associated with immune infiltration that may be involved in the immunotherapy response in LUAD. However, the related mechanism needs further research.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/metabolismo , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Prognóstico , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismo , Microambiente Tumoral/genética
10.
Med Sci (Basel) ; 10(2)2022 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-35736349

RESUMO

Evidence continues to emerge that the social determinants of health play a role in adverse outcomes related to COVID-19, including increased morbidity and mortality, increased risk of long COVID, and vaccine adverse effects. Therefore, a more nuanced understanding of the biochemical and cellular pathways of illnesses commonly associated with adverse social determinants of health is urgently needed. We contend that a commitment to understanding adverse outcomes in historically marginalized communities will increase community-level confidence in public health measures. Here, we synthesize emerging literature on mast cell disease, and the role of mast cells in chronic illness, alongside emerging research on mechanisms of COVID illness and vaccines. We propose that a focus on aberrant and/or hyperactive mast cell behavior associated with chronic underlying health conditions can elucidate adverse COVID-related outcomes and contribute to the pandemic recovery. Standards of care for mast cell activation syndrome (MCAS), as well as clinical reviews, experimental research, and case reports, suggest that effective and cost-efficient remedies are available, including antihistamines, vitamin C, and quercetin, among others. Primary care physicians, specialists, and public health workers should consider new and emerging evidence from the biomedical literature in tackling COVID-19. Specialists and researchers note that MCAS is likely grossly under-diagnosed; therefore, public health agencies and policy makers should urgently attend to community-based experiences of adverse COVID outcomes. It is essential that we extract and examine experiential evidence of marginalized communities from the broader political-ideological discourse.


Assuntos
COVID-19 , COVID-19/complicações , Humanos , Mastócitos , Pandemias , Determinantes Sociais da Saúde
11.
Technol Cancer Res Treat ; 21: 15330338221106530, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35730194

RESUMO

Objectives: Research on the role of mast cells (MCs) in cervical tumor immunity is more limited. Therefore, our study aimed to evaluate the prognostic value of MCs and their correlation with the immune microenvironment of cervical carcinoma (CC). Methods: The Cancer Genome Atlas (TCGA) data was utilized to obtain the degree of immune infiltration of MCs in CC. Meanwhile, this study retrospectively collected patient clinical characteristic data and tissue specimens to further verify the relevant conclusions. Mast cell density (MCD) was measured by the CIBERSORT algorithm in TCGA data and immunohistochemical staining of tryptase in CC tissues. Finally, differentially expressed genes (DEGs) of TCGA data were performed using "limma" packages and key gene modules were identified using the MCODE application in Cytoscape. Results: The results showed MCs were diffusely distributed in CC tissues. Moreover, we found that low tumor-infiltrating MCD was beneficial for overall survival (OS) in the TCGA cohort. Consistent conclusions were also obtained in a clinical cohort. In addition, a total of 305 DEGs were analyzed between the high tumor-infiltrating MCD and low tumor-infiltrating MCD group. Seven key modules, a total of 34 genes, were screened through the MCODE plug-in, which was mainly related to inflammatory response and immune response and closely correlated with cytokines including CSF2, CCL20, IL1A, IL1B, and CXCL8. Conclusion: In short, high tumor-infiltration MCs in CC tissue was associated with worse OS in patients. Furthermore, MCs were closely related to cytokines in the tumor microenvironment, suggesting that they collectively played a role in the immune response of the tumor. Therefore, MCD may be a potential prognostic indicator and immunotherapy target of CC.


Assuntos
Carcinoma , Neoplasias do Colo do Útero , Biomarcadores Tumorais/genética , Carcinoma/patologia , Contagem de Células , Citocinas , Feminino , Humanos , Mastócitos/patologia , Prognóstico , Estudos Retrospectivos , Microambiente Tumoral/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
12.
Front Immunol ; 13: 886044, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35720353

RESUMO

The immunologic mechanisms that contribute to the response to Mycobacterium tuberculosis infection still represent a challenge in the clinical management and scientific understanding of tuberculosis disease. In this scenario, the role of the different cells involved in the host response, either in terms of innate or adaptive immunity, remains key for defeating this disease. Among this coordinated cell response, mast cells remain key for defeating tuberculosis infection and disease. Together with its effector's molecules, membrane receptors as well as its anatomical locations, mast cells play a crucial role in the establishment and perpetuation of the inflammatory response that leads to the generation of the granuloma during tuberculosis. This review highlights the current evidences that support the notion of mast cells as key link to reinforce the advancements in tuberculosis diagnosis, disease progression, and novel therapeutic strategies. Special focus on mast cells capacity for the modulation of the inflammatory response among patients suffering multidrug resistant tuberculosis or in co-infections such as current COVID-19 pandemic.


Assuntos
COVID-19 , Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Humanos , Imunidade Inata , Mastócitos , Pandemias
13.
Int J Mol Sci ; 23(11)2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35682552

RESUMO

Immune-mediated cholangiopathies are characterised by the destruction of small and large bile ducts causing bile acid stasis, which leads to subsequent inflammation, fibrosis, and eventual cirrhosis of the liver tissue. A breakdown of peripheral hepatic immune tolerance is a key feature of these diseases. Regulatory T cells (Tregs) are a major anti-inflammatory immune cell subset, and their quantities and functional capacity are impaired in autoimmune liver diseases. Tregs can undergo phenotypic reprogramming towards pro-inflammatory Th1 and Th17 profiles. The inflamed hepatic microenvironment influences and can impede normal Treg suppressive functions. Mast cell (MC) infiltration increases during liver inflammation, and active MCs have been shown to be an important source of pro-inflammatory mediators, thus driving pathogenesis. By influencing the microenvironment, MCs can indirectly manipulate Treg functions and inhibit their suppressive and proliferative activity. In addition, direct cell-to-cell interactions have been identified between MCs and Tregs. It is critical to consider the effects of MCs on the inflammatory milieu of the liver and their influence on Treg functions. This review will focus on the roles and crosstalk of Tregs and MCs during autoimmune cholangiopathy pathogenesis progression.


Assuntos
Mastócitos , Linfócitos T Reguladores , Fibrose , Humanos , Inflamação/patologia , Fígado/patologia , Células Th17
14.
Molecules ; 27(11)2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35684410

RESUMO

Pseudoallergic reactions are hypersensitivity reactions mediated by an IgE-independent mechanism. Since allantoin (AT)-mediated pseudoallergy has not been studied, in this study, our objective is to investigate the anti-pseudoallergy effect of AT and its underlying mechanism. In vitro, ß-hexosaminidase (ß-Hex) and histamine (HIS) release assays, inflammatory cytokine assays, toluidine blue staining, and F-actin microfilament staining were used to evaluate the inhibitory effect of AT in RBL-2H3 cells stimulated with Compound 48/80 (C48/80). Western blot analysis is further performed to investigate intracellular calcium fluctuation-related signaling pathways. In vivo, Evans Blue extraction, paw swelling, and the diameter of Evans Blue extravasation were evaluated, and skin tissues are examined for histopathological examination in mice with passive cutaneous anaphylaxis (PCA) induced by C48/80. Body temperature is measured, and the levels of cytokines are further determined by ELISA kits in mice with active systemic anaphylaxis (ASA) induced by C48/80. The results show that AT dose-dependently inhibited degranulation in C48/80-stimulated RBL-2H3 cells by inhibiting ß-Hex and HIS release, reducing the levels of TNF-α, IL-8, and MCP-1, inhibiting shape changes due to degranulation and disassembling the F-actin cytoskeleton. Furthermore, AT dose-dependently inhibits the phosphorylation of PLCγ and IP3R. In vivo, AT decreased Evans Blue extravasation, paw swelling, and the diameter of Evans Blue extravasation and significantly ameliorate pathological changes and mast cell degranulation in C48/80-induced PCA. Furthermore, AT help the mice recover from the C48/80-induced decrease in body temperature and decreased the levels of cytokines in C48/80-treated ASA mice. Our results indicate that allantoin inhibits compound 48/80-induced pseudoallergic reactions. AT has the potential to be used in IgE-independent anti-allergic and anti-inflammatory therapies.


Assuntos
Anafilaxia , p-Metoxi-N-metilfenetilamina , Alantoína/metabolismo , Anafilaxia/induzido quimicamente , Anafilaxia/tratamento farmacológico , Anafilaxia/metabolismo , Animais , Degranulação Celular , Citocinas/metabolismo , Edema/patologia , Azul Evans/efeitos adversos , Azul Evans/metabolismo , Imunoglobulina E/metabolismo , Mastócitos , Camundongos , beta-N-Acetil-Hexosaminidases/metabolismo , p-Metoxi-N-metilfenetilamina/efeitos adversos
15.
Biomed Pharmacother ; 150: 113014, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35658248

RESUMO

Propofol (PPF) has a protective effect on myocardial ischemia-reperfusion (I/R) injury (MIRI). The purpose of this study was to investigate whether the myocardial protective effect of propofol is related to the inhibition of mast cell degranulation and explore the possible mechanisms involved. Our in vivo results showed that compared with the sham group, cardiac function, infarct size, histopathological damage, apoptosis, and markers of myocardial necrosis were significantly increased in the ischemia-reperfusion group, and propofol pretreatment alleviated these effects. In the coculture system, propofol-treated mast cells reduced their tryptase activity, resulting in cardiomyocyte protective effects, such as decreased apoptosis of cardiomyocytes and decreased expression of myocardial necrosis markers. Finally, experimental results in vitro revealed that thapsigargin (TG) can increase mast cell degranulation, tryptase release, calcium ion concentration, and the expression of STIM1 and Orai1 induced by H/R, but propofol pretreatment can partially reverse the above effects. These results suggested that the cardioprotective effect of propofol is achieved in part by inhibiting calcium influx through store-operated Ca2+ channels (SOCs) and thus alleviating mast cell degranulation.


Assuntos
Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Propofol , Animais , Apoptose , Cálcio/metabolismo , Degranulação Celular , Mastócitos , Infarto do Miocárdio/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/patologia , Propofol/farmacologia , Ratos , Ratos Sprague-Dawley , Triptases/metabolismo , Triptases/farmacologia
16.
Acta Vet Scand ; 64(1): 14, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761297

RESUMO

BACKGROUND: Mast cell density has been shown to have both enhancing and inhibiting effects on tumour progression and the ability to predict breast cancer behaviour in humans. However, prognostic results have been contradictory. Some previous studies suggested involvement of mast cells in the progression of canine mammary tumours. This study investigated total, intratumoural and peritumoural mast cell densities by Giemsa staining, and their association with clinicopathological parameters and the disease outcome of canine mammary tumours. In addition, since mast cells promote angiogenesis, the microvascular density and endothelial area were evaluated by CD31 immunostaining. RESULTS: Intratumoural mast cell density was associated with tumour size, lymph node involvement and tumour-infiltrating lymphocyte count, while peritumoural mast cell density was associated with grade. The endothelial area was associated with grade, mitotic index, tubular formation and proliferation index. Tumours with a high grade, high total intratumoural mast cell density and a larger endothelial area were associated with shorter disease-free survival. Intratumoural mast cell density and grade were found to be independent prognostic factors. CONCLUSIONS: These results suggest that intratumoural mast cell density and the endothelial area can be used to evaluate the aggressiveness of canine mammary carcinomas, while intratumoural mast cell density could be of use as an independent predictor of a prognosis of disease-free survival. Peritumoural mast cell density does not seem to influence tumour behaviour.


Assuntos
Carcinoma , Doenças do Cão , Neoplasias Mamárias Animais , Mastócitos , Animais , Carcinoma/veterinária , Contagem de Células/veterinária , Doenças do Cão/diagnóstico , Doenças do Cão/patologia , Cães , Feminino , Neoplasias Mamárias Animais/diagnóstico , Neoplasias Mamárias Animais/patologia , Mastócitos/patologia , Densidade Microvascular , Prognóstico
17.
Ann Lab Med ; 42(6): 678-682, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-35765876

RESUMO

Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Mastocitose Sistêmica , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Neoplasias Hematológicas/complicações , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Mastócitos , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/tratamento farmacológico , Proteína 1 Parceira de Translocação de RUNX1/genética , Coloração e Rotulagem
18.
J Immunol Res ; 2022: 5414993, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35769512

RESUMO

Sustaining higher frequency of mast cells in the allergic lesion site has been recognized. Factors causing high numbers of mast cells in the local tissues are not fully understood yet. RAS signaling plays a role in sustaining certain cell activities. This study is aimed at elucidating the role of RAS activation in the apoptosis resistance induction in mast cells and at employing semaphorin 3A to regulate RAS activities in sensitized mast cells and alleviating the allergic response in the intestine. A food allergy (FA) mouse model was developed. Mast cells were isolated from FA mouse intestinal tissues by flow cytometry. Mast cell apoptosis was assessed by staining with annexin V and propidium iodide. We found that aberrantly higher p21-activated kinase-1 (Pak1) expression in FA mast cells was associated with mast cell aggregation in the intestine. Sensitization increased Pak1 expression and apoptosis resistance in intestinal mast cells. RAS and Pak1 mutually potentiated each other in sensitized mast cells. Semaphorin 3A (sema3A) suppressed the Pak1 expression and RAS activation in mast cells. sema3A restored the apoptosis sensitivity in sensitized mast cells. Administration of sema3A potentiated allergen-specific immunotherapy in experimental FA. In conclusion, mast cells of FA mice showed higher Pak1 expression and high RAS activation status that contributed to apoptosis resistance in mast cells. Administration of sema3A restored the sensitivity to apoptosis inducers and promoted the therapeutic effects of specific immunotherapy on experimental FA.


Assuntos
Hipersensibilidade Alimentar , Semaforinas , Animais , Dessensibilização Imunológica , Hipersensibilidade Alimentar/terapia , Fatores Imunológicos , Mastócitos/fisiologia , Camundongos , Semaforina-3A/metabolismo , Semaforinas/metabolismo
19.
Front Immunol ; 13: 898419, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634300

RESUMO

Skin is a frontline organ that is continuously exposed to external stimuli, including pathogens. Various immune cells reside in the skin under physiological conditions and protect the body from the entry of pathogens/antigens by interacting with each other and orchestrating diverse cutaneous immune responses. To avoid unnecessary inflammation and tissue damage during the elimination of external pathogens and antigens, skin possesses regulatory systems that fine-tune these immune reactions. Mast cells (MCs) are one of the skin-resident immune cell populations that play both effector and regulatory functions in the cutaneous immune response. So far, the interleukin-10-mediated mechanisms have mostly been investigated as the regulatory mechanisms of MCs. Recent studies have elucidated other regulatory mechanisms of MCs, such as the maintenance of regulatory T/B cells and the programmed cell death protein-1/programmed cell death-ligand 1-mediated inhibitory pathway. These regulatory pathways of MCs have been suggested to play important roles in limiting the excessive inflammation in inflammatory skin diseases, such as contact and atopic dermatitis. The regulatory functions of MCs may also be involved in the escape mechanisms of antitumor responses in skin cancers, such as melanoma. Understanding and controlling the regulatory functions of skin MCs may lead to novel therapeutic strategies for inflammatory skin diseases and skin cancers.


Assuntos
Dermatite Atópica , Neoplasias Cutâneas , Humanos , Imunidade , Inflamação , Mastócitos
20.
Nat Commun ; 13(1): 3013, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35641514

RESUMO

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-ß signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.


Assuntos
Ácidos Graxos Ômega-3 , Hipertensão Pulmonar , Animais , Compostos de Epóxi/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Humanos , Hipertensão Pulmonar/patologia , Mastócitos/patologia , Camundongos , Remodelação Vascular
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