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2.
Immunohorizons ; 8(6): 431-441, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38888412

RESUMO

IgE-mediated mast cell (MC) activation is a critical component of allergic responses to oral Ags. Several T cell-derived cytokines have been shown to promote MC reactivity, and we recently demonstrated a critical role for the cytokine IL-10 in mediating MC responses during food allergy. In this study, we further validate the role of IL-10 using Ab-mediated IL-10 depletion. IL-10 neutralization significantly attenuated MC responses, leading to decreased MC accumulation and activation, as well as inhibition of MC-mediated symptoms such as allergic diarrhea. This was accompanied by decreased Th2 cytokine gene expression, attenuated systemic T cell responses, and fewer CD4 T cells, B cells, and MCs in the spleen. Our data further confirm the role of IL-10 in driving MC responses and suggest that IL-10-responsive MCs may constitute an important player in allergic responses.


Assuntos
Modelos Animais de Doenças , Hipersensibilidade Alimentar , Interleucina-10 , Mastócitos , Animais , Feminino , Camundongos , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/imunologia , Interleucina-10/metabolismo , Mastócitos/imunologia , Mastócitos/metabolismo , Camundongos Endogâmicos BALB C , Baço/imunologia , Baço/citologia , Células Th2/imunologia , Masculino
3.
J Immunol ; 212(9): 1407-1419, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38497670

RESUMO

Mast cells (MCs) play critical roles in the establishment of allergic diseases. We recently demonstrated an unexpected, proinflammatory role for IL-10 in regulating MC responses. IL-10 enhanced MC activation and promoted IgE-dependent responses during food allergy. However, whether these effects extend to IgE-independent stimuli is not clear. In this article, we demonstrate that IL-10 plays a critical role in driving IL-33-mediated MC responses. IL-10 stimulation enhanced MC expansion and degranulation, ST2 expression, IL-13 production, and phospho-relA upregulation in IL-33-treated cells while suppressing TNF-α. These effects were partly dependent on endogenous IL-10 and further amplified in MCs coactivated with both IL-33 and IgE/Ag. IL-10's divergent effects also extended in vivo. In a MC-dependent model of IL-33-induced neutrophilia, IL-10 treatment enhanced MC responsiveness, leading to suppression of neutrophils and decreased TNF-α. In contrast, during IL-33-induced type 2 inflammation, IL-10 priming exacerbated MC activity, resulting in MC recruitment to various tissues, enhanced ST2 expression, induction of hypothermia, recruitment of eosinophils, and increased MCPT-1 and IL-13 levels. Our data elucidate an important role for IL-10 as an augmenter of IL-33-mediated MC responses, with implications during both allergic diseases and other MC-dependent disorders. IL-10 induction is routinely used as a prognostic marker of disease improvement. Our data suggest instead that IL-10 can enhance ST2 responsiveness in IL-33-activated MCs, with the potential to both aggravate or suppress disease severity depending on the inflammatory context.


Assuntos
Hipersensibilidade Alimentar , Mastócitos , Humanos , Mastócitos/metabolismo , Interleucina-10/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Imunoglobulina E/metabolismo , Interleucina-33/metabolismo , Interleucina-13/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Inflamação/metabolismo , Degranulação Celular
4.
Nat Cell Biol ; 25(12): 1860-1872, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37973841

RESUMO

Intracellular surveillance for systemic microbial components during homeostasis and infections governs host physiology and immunity. However, a long-standing question is how circulating microbial ligands become accessible to intracellular receptors. Here we show a role for host-derived extracellular vesicles (EVs) in this process; human and murine plasma-derived and cell culture-derived EVs have an intrinsic capacity to bind bacterial lipopolysaccharide (LPS). Remarkably, circulating host EVs capture blood-borne LPS in vivo, and the LPS-laden EVs confer cytosolic access for LPS, triggering non-canonical inflammasome activation of gasdermin D and pyroptosis. Mechanistically, the interaction between the lipid bilayer of EVs and the lipid A of LPS underlies EV capture of LPS, and the intracellular transfer of LPS by EVs is mediated by CD14. Overall, this study demonstrates that EVs capture and escort systemic LPS to the cytosol licensing inflammasome responses, uncovering EVs as a previously unrecognized link between systemic microbial ligands and intracellular surveillance.


Assuntos
Vesículas Extracelulares , Inflamassomos , Humanos , Animais , Camundongos , Inflamassomos/metabolismo , Lipopolissacarídeos , Caspases/metabolismo , Piroptose , Citosol , Vesículas Extracelulares/metabolismo
5.
J Neuroinflammation ; 18(1): 296, 2021 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-34933669

RESUMO

BACKGROUND: Tight junctions (TJs) are membrane specializations characteristic of barrier-forming membranes, which function to seal the aqueous pathway between endothelial cells or epithelial cells and, thereby, obstruct intercellular solute and cellular movement. However, previous work from our laboratory found that claudin-5 (CLN-5), a TJ protein prominent at the blood-brain barrier (BBB), was also detected, ectopically, on leukocytes (CLN-5+) in the blood and central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE), a neuroinflammatory, demyelinating disease that is a model for multiple sclerosis. CLN-5 was further shown to be transferred from endothelial cells to circulating leukocytes during disease, prompting consideration this action is coupled to leukocyte transendothelial migration (TEM) into the CNS by fostering transient interactions between corresponding leukocyte and endothelial junctional proteins at the BBB. METHODS: To begin clarifying the significance of CLN-5+ leukocytes, flow cytometry was used to determine their appearance in the blood and CNS during EAE. RESULTS: Flow cytometric analysis revealed CLN-5+ populations among CD4 and CD8 T cells, B cells, monocytes and neutrophils, and these appeared with varying kinetics and to different extents in both blood and CNS. CLN-5 levels on circulating T cells further correlated highly with activation state. And, the percentage of CLN-5+ cells among each of the subtypes analyzed was considerably higher in CNS tissue than in blood, consistent with the interpretation that CLN-5+ leukocytes gain preferred access to the CNS. CONCLUSION: Several leukocyte subtypes variably acquire CLN-5 in blood before they enter the CNS, an event that may represent a novel mechanism to guide leukocytes to sites for paracellular diapedesis across the BBB.


Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Claudina-5/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Leucócitos/patologia , Animais , Barreira Hematoencefálica/metabolismo , Claudina-5/sangue , Claudina-5/metabolismo , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias/genética , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Proteínas de Junções Íntimas/metabolismo
6.
Front Immunol ; 11: 606837, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33414789

RESUMO

The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.


Assuntos
Antialérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Hipersensibilidade Alimentar/prevenção & controle , Imunoglobulina E/metabolismo , Intestinos/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Isomerases de Dissulfetos de Proteínas/antagonistas & inibidores , Animais , Bacitracina/farmacologia , Degranulação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Curcumina/farmacologia , Citocinas/metabolismo , Diarreia/enzimologia , Diarreia/imunologia , Diarreia/prevenção & controle , Modelos Animais de Doenças , Hipersensibilidade Alimentar/enzimologia , Hipersensibilidade Alimentar/imunologia , Intestinos/enzimologia , Intestinos/imunologia , Mastócitos/enzimologia , Mastócitos/imunologia , Camundongos Endogâmicos BALB C , Ovalbumina , Isomerases de Dissulfetos de Proteínas/metabolismo , Rutina/farmacologia , Transdução de Sinais
7.
Front Immunol ; 9: 2414, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405614

RESUMO

Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation, and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-α, and IL-13. In contrast, pretreatment with TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FcεRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, continuous TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed an increase in I-κBα and a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in enhancement of I-κBα transcription and decreased NF-κB activation. Lastly, treatment of wild-type mice with TSA in a model of ovalbumin-induced food allergy resulted in a significant attenuation in the development of food allergy symptoms including decreases in allergic diarrhea and mast cell activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via altered histone acetylation, and that exposure to dietary substances may induce epigenetic modifications that modulate mast cell function.


Assuntos
Hipersensibilidade Alimentar/imunologia , Histonas/metabolismo , Mastócitos/imunologia , Acetilação , Animais , Apoptose , Células da Medula Óssea/citologia , Degranulação Celular , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Hipersensibilidade Alimentar/genética , Regulação da Expressão Gênica , Inibidores de Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/metabolismo , Imunoglobulina E/metabolismo , Camundongos , NF-kappa B/metabolismo
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