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1.
Front Immunol ; 12: 650331, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777047

RESUMO

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents a global health crisis. Immune cell activation via pattern recognition receptors has been implicated as a driver of the hyperinflammatory response seen in COVID-19. However, our understanding of the specific immune responses to SARS-CoV-2 remains limited. Mast cells (MCs) and eosinophils are innate immune cells that play pathogenic roles in many inflammatory responses. Here we report MC-derived proteases and eosinophil-associated mediators are elevated in COVID-19 patient sera and lung tissues. Stimulation of viral-sensing toll-like receptors in vitro and administration of synthetic viral RNA in vivo induced features of hyperinflammation, including cytokine elevation, immune cell airway infiltration, and MC-protease production-effects suppressed by an anti-Siglec-8 monoclonal antibody which selectively inhibits MCs and depletes eosinophils. Similarly, anti-Siglec-8 treatment reduced disease severity and airway inflammation in a respiratory viral infection model. These results suggest that MC and eosinophil activation are associated with COVID-19 inflammation and anti-Siglec-8 antibodies are a potential therapeutic approach for attenuating excessive inflammation during viral infections.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos B/imunologia , Eosinófilos/imunologia , Lectinas/imunologia , Mastócitos/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Receptores Toll-Like/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/metabolismo , /prevenção & controle , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Eosinófilos/virologia , Interações Hospedeiro-Patógeno , Humanos , Lectinas/antagonistas & inibidores , Lectinas/genética , Lectinas/metabolismo , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Mastócitos/virologia , Camundongos Transgênicos , Peptídeo Hidrolases/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Infecções por Vírus Respiratório Sincicial/virologia , Receptores Toll-Like/metabolismo
2.
Front Immunol ; 12: 640093, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717193

RESUMO

COVID-19 (SARS-CoV-2) disease severity and stages varies from asymptomatic, mild flu-like symptoms, moderate, severe, critical, and chronic disease. COVID-19 disease progression include lymphopenia, elevated proinflammatory cytokines and chemokines, accumulation of macrophages and neutrophils in lungs, immune dysregulation, cytokine storms, acute respiratory distress syndrome (ARDS), etc. Development of vaccines to severe acute respiratory syndrome (SARS), Middle East Respiratory Syndrome coronavirus (MERS-CoV), and other coronavirus has been difficult to create due to vaccine induced enhanced disease responses in animal models. Multiple betacoronaviruses including SARS-CoV-2 and SARS-CoV-1 expand cellular tropism by infecting some phagocytic cells (immature macrophages and dendritic cells) via antibody bound Fc receptor uptake of virus. Antibody-dependent enhancement (ADE) may be involved in the clinical observation of increased severity of symptoms associated with early high levels of SARS-CoV-2 antibodies in patients. Infants with multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 may also have ADE caused by maternally acquired SARS-CoV-2 antibodies bound to mast cells. ADE risks associated with SARS-CoV-2 has implications for COVID-19 and MIS-C treatments, B-cell vaccines, SARS-CoV-2 antibody therapy, and convalescent plasma therapy for patients. SARS-CoV-2 antibodies bound to mast cells may be involved in MIS-C and multisystem inflammatory syndrome in adults (MIS-A) following initial COVID-19 infection. SARS-CoV-2 antibodies bound to Fc receptors on macrophages and mast cells may represent two different mechanisms for ADE in patients. These two different ADE risks have possible implications for SARS-CoV-2 B-cell vaccines for subsets of populations based on age, cross-reactive antibodies, variabilities in antibody levels over time, and pregnancy. These models place increased emphasis on the importance of developing safe SARS-CoV-2 T cell vaccines that are not dependent upon antibodies.


Assuntos
Anticorpos Facilitadores , Mastócitos/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Fagócitos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Animais , Anticorpos Antivirais/metabolismo , Criança , Reações Cruzadas , Feminino , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Modelos Imunológicos , Gravidez , Receptores Fc/metabolismo , Risco , Linfócitos T/imunologia
3.
Nat Commun ; 12(1): 346, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436641

RESUMO

Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Linfócitos do Interstício Tumoral/imunologia , Mastócitos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
5.
Nat Commun ; 12(1): 494, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479210

RESUMO

Mast cells are critical effectors of allergic inflammation and protection against parasitic infections. We previously demonstrated that transcription factors GATA2 and MITF are the mast cell lineage-determining factors. However, it is unclear whether these lineage-determining factors regulate chromatin accessibility at mast cell enhancer regions. In this study, we demonstrate that GATA2 promotes chromatin accessibility at the super-enhancers of mast cell identity genes and primes both typical and super-enhancers at genes that respond to antigenic stimulation. We find that the number and densities of GATA2- but not MITF-bound sites at the super-enhancers are several folds higher than that at the typical enhancers. Our studies reveal that GATA2 promotes robust gene transcription to maintain mast cell identity and respond to antigenic stimulation by binding to super-enhancer regions with dense GATA2 binding sites available at key mast cell genes.


Assuntos
Antígenos/metabolismo , Montagem e Desmontagem da Cromatina/genética , Elementos Facilitadores Genéticos/genética , Fator de Transcrição GATA2/genética , Mastócitos/metabolismo , Animais , Antígenos/imunologia , Linhagem da Célula/genética , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Feminino , Fator de Transcrição GATA2/metabolismo , Perfilação da Expressão Gênica/métodos , Masculino , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo
7.
Phytomedicine ; 80: 153391, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33113502

RESUMO

BACKGROUND: Pseudo-allergic reactions are potentially fatal hypersensitivity responses caused by mast cell activation. α-linolenic acid (ALA) is known for its anti-allergic properties. However, its potential anti-pseudo-allergic effects were not much investigated. PURPOSE: To investigate the inhibitory effects of ALA on IgE-independent allergy in vitro, and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of ALA was evaluated in passive cutaneous anaphylaxis reaction (PCA) and systemic anaphylaxis models. Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. RESULTS: ALA (0, 1.0, 2.0, and 4.0 mg/kg) dose-dependently reduced serum histamine, chemokine release, vasodilation, eosinophil infiltration, and the percentage of degranulated mast cells in C57BL/6 mice. In addition, ALA (0, 50, 100, and 200 µM) reduced Compound 48/80 (C48/80) (30 µg/ml)-or Substance P (SP) (4 µg/ml)-induced calcium influx, mast cell degranulation and cytokines and chemokine release in Laboratory of Allergic Disease 2 (LAD2) cells via Lyn-PLCγ-IP3R-Ca2+ and Lyn-p38/NF-κB signaling pathway. Moreover, ALA (0, 50, 100, and 200 µM) inhibited C48/80 (30 µg/ml)- and SP (4 µg/ml)-induced calcium influx in Mas-related G-protein coupled receptor member X2 (MrgX2)-HEK293 cells and in vitro kinase assays confirmed that ALA inhibited the activity of Lyn kinase. In response to 200 µM of ALA, the activity of Lyn kinase by (7.296 ± 0.03751) × 10-5 units/µl and decreased compared with C48/80 (30 µg/ml) by (8.572 ± 0.1365) ×10-5 units/µl. CONCLUSION: Our results demonstrate that ALA might be a potential Lyn kinase inhibitor, which could be used to treat pseudo-allergic reaction-related diseases such as urticaria.


Assuntos
Anafilaxia/tratamento farmacológico , Antialérgicos/farmacologia , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Ácido alfa-Linoleico/farmacologia , Quinases da Família src/antagonistas & inibidores , Animais , Degranulação Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Relação Dose-Resposta a Droga , Humanos , Imunoglobulina E/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores de Neuropeptídeos/metabolismo , p-Metoxi-N-metilfenetilamina/toxicidade , Quinases da Família src/química , Quinases da Família src/imunologia , Quinases da Família src/metabolismo
8.
Life Sci ; 266: 118906, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33338502

RESUMO

AIMS: The aim of this study was to investigate the role of TRPA1 in the pathogenesis of AD. MAIN METHODS: The experimental atopic dermatitis (AD)-like skin lesions were established using 2,4-dinitrochlorobenzene (DNCB). Mice were divided into three groups: TRPA1-/- and WT groups were treated with DNCB dissolved in a 3:1 mixture of acetone and olive oil; the negative control group was treated with 3:1 mixture of acetone and olive oil without DNCB. The treatment lasted for 21 days, after which the animals were sacrificed and their blood, ears and dorsal skin tissue samples were collected for analysis. KEY FINDINGS: Lower dermatitis score, ear thickness, pruritus score, and epidermal hyperplasia were observed in mice in TRPA1-/- mice compared to the WT group. Besides, lower dermal mast cell infiltration, proinflammatory cytokines, Th2 cytokines and the infiltration of macrophages were observed in the TRPA1-/- mice compared to the WT group. Furthermore, we demonstrated that TRPA1 antagonist HC-030031 could alleviate AD-like symptoms and reduce the degree of epidermal hyperplasia in mice. SIGNIFICANCE: TRPA1 has a crucial role during the AD pathogenesis in mice, thus may be used as a potential new target for treating patients with chronic skin inflammatory disease.


Assuntos
Dermatite Atópica/complicações , Inflamação/prevenção & controle , Macrófagos/imunologia , Mastócitos/imunologia , Prurido/prevenção & controle , Canal de Cátion TRPA1/fisiologia , Acetanilidas/farmacologia , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/patologia , Dinitroclorobenzeno/toxicidade , Inflamação/etiologia , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prurido/etiologia , Prurido/patologia , Purinas/farmacologia , Canal de Cátion TRPA1/antagonistas & inibidores
9.
PLoS Pathog ; 16(12): e1009121, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351862

RESUMO

Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1+ cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity.


Assuntos
Interleucina-33/imunologia , Interleucina-9/imunologia , Enteropatias Parasitárias/imunologia , Linfócitos/imunologia , Mastócitos/imunologia , Estrongiloidíase/imunologia , Animais , Imunidade Inata/imunologia , Intestinos/imunologia , Intestinos/parasitologia , Camundongos , Strongyloides ratti/imunologia
10.
Int J Mol Sci ; 21(24)2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33353063

RESUMO

Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field.


Assuntos
Cicatriz/etiologia , Cicatriz/metabolismo , Fibrose/etiologia , Fibrose/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Animais , Biomarcadores , Comunicação Celular , Cicatriz/patologia , Cicatriz Hipertrófica , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fibroblastos/metabolismo , Fibrose/patologia , Humanos , Queloide , Mecanotransdução Celular
11.
Front Immunol ; 11: 574862, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042157

RESUMO

It is currently believed that innate immunity is unable to prevent the spread of SARS-CoV-2 from the upper airways to the alveoli of high-risk groups of patients. SARS-CoV-2 replication in ACE-2-expressing pneumocytes can drive the diffuse alveolar injury through the cytokine storm and immunothrombosis by upregulating the transcription of chemokine/cytokines, unlike several other respiratory viruses. Here we report histopathology data obtained in post-mortem lung biopsies of COVID-19, showing the increased density of perivascular and septal mast cells (MCs) and IL-4-expressing cells (n = 6), in contrast to the numbers found in pandemic H1N1-induced pneumonia (n = 10) or Control specimens (n = 10). Noteworthy, COVID-19 lung biopsies showed a higher density of CD117+ cells, suggesting that c-kit positive MCs progenitors were recruited earlier to the alveolar septa. These findings suggest that MC proliferation/differentiation in the alveolar septa might be harnessed by the shift toward IL-4 expression in the inflamed alveolar septa. Future studies may clarify whether the fibrin-dependent generation of the hyaline membrane, processes that require the diffusion of procoagulative plasma factors into the alveolar lumen and the endothelial dysfunction, are preceded by MC-driven formation of interstitial edema in the alveolar septa.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Mastócitos/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Edema Pulmonar/imunologia , Trombose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana/imunologia , Influenza Humana/patologia , Influenza Humana/virologia , Interleucina-4/imunologia , Masculino , Mastócitos/patologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas c-kit/imunologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/virologia , Edema Pulmonar/patologia , Edema Pulmonar/virologia , Trombose/patologia , Trombose/virologia
12.
Drug Discov Ther ; 14(5): 259-261, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33116043

RESUMO

Regardless of the severity of coronavirus disease 2019 (COVID-19), a high proportion of patients struggle with persistent respiratory or systemic symptoms after recovery. This is called "postCOVID syndrome", for which pulmonary fibrosis is one of the pathogenesis. Besides T-lymphocytes and macrophages, mast cells also contribute to the development of cytokine storm and thus stimulate the activity of fibroblasts. Additionally, by the exocytotic release of fibroblast-activating factors, mast cells directly facilitate the progression of pulmonary fibrosis. In our previous basic studies, anti-allergic drugs (olopatadine, ketotifen), antibiotics (clarithromycin) and corticosteroids (hydrocortisone, dexamethasone) inhibited the process of exocytosis and showed their potency as highly effective mast cell stabilizers. Given such pharmacological properties of these commonly used drugs, they may be useful in the treatment of post-COVID-19 pulmonary fibrosis and in relieving the symptoms of post-COVID syndrome.


Assuntos
Corticosteroides/uso terapêutico , Antialérgicos/uso terapêutico , Antibacterianos/uso terapêutico , Betacoronavirus/patogenicidade , Degranulação Celular/efeitos dos fármacos , Infecções por Coronavirus/virologia , Mastócitos/efeitos dos fármacos , Pneumonia Viral/virologia , Fibrose Pulmonar/tratamento farmacológico , Animais , Infecções por Coronavirus/imunologia , Interações Hospedeiro-Patógeno , Humanos , Mastócitos/imunologia , Mastócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/virologia
13.
Clin Ther ; 42(10): 1850-1852, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32883529

RESUMO

Recent articles have reported elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased patients with coronavirus 2019 (COVID-19). Platelets are critical in the formation of thrombi, and their most potent trigger is platelet activating factor (PAF). PAF is produced by cells involved in host defense, and its biological actions bear similarities with COVID-19 disease manifestations, including pulmonary microthromboses and inflammation, possibly via activation of mast cells. The histamine1 receptor antagonist rupatadine was developed to have anti-PAF activity and inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis.


Assuntos
Infecções por Coronavirus , Pandemias , Fator de Ativação de Plaquetas , Pneumonia Viral , Trombose , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Mastócitos/imunologia , Agregação Plaquetária/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia
14.
Psychiatr Danub ; 32(Suppl 1): 93-104, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32890371

RESUMO

Mechanisms of cortical psychoses are approached by complementing big data-driven genetics and imaging with a putatively subverted neurovascular "reverse plumbing" by arteries. The "cortical spread" of grey matter loss in schizophrenia and the mid-pericallosal "congestion" in fMRI of periodic catatonia - treatable electromagnetically along arteries - are interpreted in terms of the fastest interstitial outflow through the Cerebral IntraMural Reverse Arterial Flow-engine (CIMURAF, Treviranus 2018-19) draining "waste" via arterio-adventitial lymphatics to the neck. Such repetitively sliding segments of CIMURAF are wrung downstream by muscles likely steered by the neurovascular pterygopalatine ganglion. At the pericallosal artery, along its ideal long straight segment, this likely happens diverging from the mid-callosum towards the front and the back. In the case of a convergent inversion a mid-callosal clash will result, which is observable in psychoses as a mid-callosal high-flow-spot simultaneously with hyper-perfusions of branches and "backwatering" of pial vessels with reactive waste - till date interpreted psycho-mathematically. CIMURAF might also accelerate the perivascular intrusion of MCs by flushing autocrine signals (of which electro-magnetism moves the dipoles) through a putative periadventitial counter-current. Psychoses plausible occur through tryptase-mediated attacks operated by mast cells against oligodendrocytes' cytoskeleton (Medic 2009) and probably via complement-4 (Schizophrenia WG, 2014) against neurons. Usually MCs are essential long-lived "orchestrators" of homeostases and immune or barrier defences interacting with nerves, immunocytes, organs, and routes. MCs after somatic programming as to "destination & destiny" (Treviranus 2017a, 6.2., 2018) rapidly intrude also into the brain's parenchyma, first within the lymphatics and then putatively by crossing-over to extraluminal arterial routes. MCs transverse the BBBs, while macrophages only trespass in "disease" (Faraco et al. 2017). Both can be "subverted" by a list of microbes (and putatively blown up by COVID-19 within walls). Enuresis and MCs' reactions to clozapine add to the interactive support from (epi-)genetics and imaging.


Assuntos
Mastócitos/imunologia , Transtornos Psicóticos/imunologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Infecções por Coronavirus , Gânglios , Humanos , Mastócitos/patologia , Pandemias , Pneumonia Viral
15.
Chem Biol Interact ; 330: 109248, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871113

RESUMO

Dextromethorphan (DM) is a cough suppressant available in many prescribed and over-the-counter medications. Adverse reactions induced by DM have been regularly reported, including allergic skin reactions in some cases. However, the underlying mechanisms of local anaphylaxis induced by DM have not been elucidated. In this study, we found that DM could activate mast cells to increase calcium mobilization and release ß-hexosaminidase, histamine, tumor necrosis factor-α, MCP-1, and IL-8 in a dose-dependent manner. The allergic reactions were confirmed by hind paw swelling and extravasation assay in vivo. Furthermore, DM was revealed to induce local anaphylaxis via MRGPRX2 by the mast cell-deficient kitW-sh/W-sh mice and MRGPRX2 knockdown mast cells. And the MRGPRX2-HEK293/CMC analysis and frontal analysis also showed that DM has a considerable affinity with MRGPRX2. Together, our findings suggest that close monitoring should be drawn on patients with DM for its potential anaphylaxis via MRGPRX2.


Assuntos
Anafilaxia/induzido quimicamente , Dextrometorfano/efeitos adversos , Mastócitos/efeitos dos fármacos , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Antitussígenos/efeitos adversos , Células Cultivadas , Dextrometorfano/toxicidade , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Receptores de Neuropeptídeos/metabolismo
16.
Am J Physiol Heart Circ Physiol ; 319(3): H705-H721, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32762560

RESUMO

Myeloperoxidase (MPO)-derived hypochlorous (HOCl) reacts with membrane plasmalogens to yield α-chlorofatty aldehydes such as 2-chlorofatty aldehyde (2-ClFALD) and its metabolite 2-chlorofatty acid (2-ClFA). Recent studies showed that 2-ClFALD and 2-ClFA serve as mediators of the inflammatory responses to sepsis by as yet unknown mechanisms. Since no scavenger for chlorinated lipids is available and on the basis of the well-established role of the MPO/HOCl/chlorinated lipid axis in inflammatory responses, we hypothesized that treatment with MPO inhibitors (N-acetyl lysyltyrosylcysteine amide or 4-aminobenzoic acid hydrazide) would inhibit inflammation and proinflammatory mediator expression induced by cecal ligation and puncture (CLP). We used intravital microscopy to quantify in vivo inflammatory responses in Sham and CLP rats with or without MPO inhibition. Small intestines, mesenteries, and lungs were collected to assess changes in MPO-positive staining and lung injury, respectively, as well as free 2-ClFA and proinflammatory mediators levels. CLP caused neutrophil infiltration, 2-ClFA generation, acute lung injury, leukocyte-/platelet-endothelium interactions, mast cell activation (MCA), plasminogen activator inhibitor-1 (PAI-1) production, and the expression of several cytokines, chemokines, and vascular endothelial growth factor, changes that were reduced by MPO inhibition. Pretreatment with a PAI-1 inhibitor or MC stabilizer prevented CLP-induced leukocyte-endothelium interactions and MCA, and abrogated exogenous 2-ClFALD-induced inflammatory responses. Thus, we provide evidence that MPO instigates these inflammatory changes in CLP and that chlorinated lipids may serve as a mechanistic link between the enzymatic activity of MPO and PAI-1- and mast cell-dependent adhesive interactions, providing a rationale for new therapeutic interventions in sepsis.NEW & NOTEWORTHY Using two distinct myeloperoxidase (MPO) inhibitors, we show for the first time that MPO plays an important role in producing increases in free 2-chlorofatty aldehyde (2-ClFALD)-a powerful proinflammatory chlorinated lipid in plasma and intestine-a number of cytokines and other inflammatory mediators, leukocyte and platelet rolling and adhesion in postcapillary venules, and lung injury in a cecal ligation and puncture model of sepsis. In addition, the use of a plasminogen activator inhibitor-1 (PAI-1) inhibitor or a mast cell stabilizer prevented inflammatory responses in CLP-induced sepsis. PAI-1 inhibition also prevented the proinflammatory responses to exogenous 2-ClFALD superfusion. Thus, our study provides some of the first evidence that MPO-derived free 2-ClFA plays an important role in CLP-induced sepsis by a PAI-1- and mast cell-dependent mechanism.


Assuntos
Ceco/microbiologia , Ácidos Graxos/metabolismo , Ácido Hipocloroso/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/enzimologia , Peroxidase/metabolismo , Sepse/enzimologia , Aldeídos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Ceco/cirurgia , Citocinas/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Intestino Delgado/enzimologia , Intestino Delgado/imunologia , Ligadura , Pulmão/enzimologia , Pulmão/imunologia , Mastócitos/enzimologia , Mastócitos/imunologia , Mesentério/enzimologia , Mesentério/imunologia , Peroxidase/antagonistas & inibidores , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Punções , Ratos Sprague-Dawley , Sepse/imunologia , Sepse/microbiologia , Sepse/prevenção & controle , Transdução de Sinais
17.
Neuroscientist ; 26(5-6): 402-414, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32684080

RESUMO

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pandemic infectious disease that originated in China. COVID-19 is a global public health emergency of international concern. COVID-19 causes mild to severe illness with high morbidity and mortality, especially in preexisting risk groups. Therapeutic options are now limited to COVID-19. The hallmark of COVID-19 pathogenesis is the cytokine storm with elevated levels of interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-alpha (TNF-α), chemokine (C-C-motif) ligand 2 (CCL2), and granulocyte-macrophage colony-stimulating factor (GM-CSF). COVID-19 can cause severe pneumonia, and neurological disorders, including stroke, the damage to the neurovascular unit, blood-brain barrier disruption, high intracranial proinflammatory cytokines, and endothelial cell damage in the brain. Mast cells are innate immune cells and also implicated in adaptive immune response, systemic inflammatory diseases, neuroinflammatory diseases, traumatic brain injury and stroke, and stress disorders. SARS-CoV-2 can activate monocytes/macrophages, dendritic cells, T cells, mast cells, neutrophils, and induce cytokine storm in the lung. COVID-19 can activate mast cells, neurons, glial cells, and endothelial cells. SARS-CoV-2 infection can cause psychological stress and neuroinflammation. In conclusion, COVID-19 can induce mast cell activation, psychological stress, cytokine storm, and neuroinflammation.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Citocinas/imunologia , Mastócitos/imunologia , Doenças do Sistema Nervoso/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Estresse Psicológico/fisiopatologia , Infecções por Coronavirus/complicações , Humanos , Mastócitos/virologia , Doenças do Sistema Nervoso/complicações , Pandemias , Pneumonia Viral/complicações
18.
Br J Anaesth ; 125(6): 970-975, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32709306

RESUMO

BACKGROUND: Immediate drug hypersensitivity reactions are an increasing public health issue and a frequent cause of life-threatening anaphylaxis. Conventional confirmatory testing include skin tests and, for a few drugs, quantification of drug-specific immunoglobulin E (IgE) antibodies. However, none of these tests are absolutely predictive for the clinical outcome, and can yield false-negative and false-positive results. We performed a proof-of-concept study to assess whether a mast cell activation test could improve diagnosis of IgE-mediated chlorhexidine hypersensitivity, a common cause of perioperative anaphylaxis. METHODS: Human mast cells were generated from CD34+ progenitor cells and sensitised with patients' sera to become IgE+ human mast cells (dMCIgE+), and then incubated with chlorhexidine to assess degranulation. We compared the diagnostic performance of this mast cell activation test with serum from patients with and without positive skin test and basophil activation test to chlorhexidine. RESULTS: In dMC sensitised with sera from patients with a positive skin test and basophil activation test to chlorhexidine showed drug-specific and concentration-dependent degranulation upon stimulation with chlorhexidine, determined by surface upregulation of the degranulation marker CD63. In contrast, dMC sensitised with sera from patients with a negative skin test and basophil activation test to chlorhexidine were unresponsive in the mast cell activation test. CONCLUSIONS: Our study suggests that the mast cell activation test can be used to diagnose IgE/FcεRI-dependent immediate drug hypersensitivity reactions. It also shows potential to assess the clinical relevance of drug-specific IgE antibodies in their ability to elicit mast cell degranulation, and therefore discriminate between allergy and sensitisation. Extended studies are required to verify whether this technique can be used in other causes of perioperative anaphylaxis.


Assuntos
Clorexidina/efeitos adversos , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade Imediata/sangue , Hipersensibilidade Imediata/diagnóstico , Mastócitos/imunologia , Adulto , Idoso , Clorexidina/imunologia , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Hipersensibilidade Imediata/imunologia , Masculino , Mastócitos/metabolismo , Pessoa de Meia-Idade
19.
Proc Natl Acad Sci U S A ; 117(30): 18068-18078, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32661165

RESUMO

Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca2+) signals. Ca2+ release from endolysosomal compartments is mediated via intracellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca2+ homeostasis and exocytosis in mast cells in vivo and ex vivo. Notably, in vivo TPC1 deficiency in mice leads to enhanced passive systemic anaphylaxis, reflected by increased drop in body temperature, most likely due to accelerated histamine-induced vasodilation. Ex vivo, mast cell-mediated histamine release and degranulation was augmented upon TPC1 inhibition, although mast cell numbers and size were diminished. Our results indicate an essential role of TPC1 in endolysosomal Ca2+ uptake and filling of endoplasmic reticulum Ca2+ stores, thereby regulating exocytosis in mast cells. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic hypersensitivity.


Assuntos
Anafilaxia/etiologia , Anafilaxia/metabolismo , Canais de Cálcio/deficiência , Suscetibilidade a Doenças , Mastócitos/imunologia , Mastócitos/metabolismo , Biomarcadores , Sinalização do Cálcio , Degranulação Celular , Citocinas/metabolismo , Predisposição Genética para Doença , Histamina/metabolismo , Imunoglobulina E/imunologia , Mediadores da Inflamação/metabolismo
20.
Ann Allergy Asthma Immunol ; 125(4): 388-392, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32687989

RESUMO

OBJECTIVE: Atopic diseases worsen with psychological stress, but how stress contributes to their pathogenesis is still not clear. We review the evidence supporting the premise that stress contributes to allergic and inflammatory processes through stimulation of mast cells (MCs) by neuroimmune stimuli. DATA SOURCES: PubMed was searched between 1950 and 2019 using the following terms: allergies, atopic diseases, corticotropin-releasing hormone, inflammation, hypothalamic-pituitary-adrenal axis, mast cells, mastocytosis, neuropeptides, psychological stress, neurotensin, and substance P. STUDY SELECTIONS: Only articles published in English were selected based on their relevance to stress and MCs, especially those that discussed potential mechanisms of action. RESULTS: Psychological stress worsens many diseases, especially asthma, atopic dermatitis, and mastocytosis. This effect is mediated through MCs stimulated by neuropeptides, especially corticotropin-releasing hormone, neurotensin, and substance P, a process augmented by interleukin-33. CONCLUSION: Understanding how stress stimulates MCs to release proinflammatory mediators is important in advancing treatments for diseases that worsen with stress.


Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/psicologia , Mastócitos/imunologia , Estresse Psicológico/imunologia , Animais , Humanos
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