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1.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638904

RESUMO

Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.


Assuntos
Imunidade Inata/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Animais , Movimento Celular/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/microbiologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/microbiologia , Transdução de Sinais/imunologia , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/fisiologia
2.
Front Immunol ; 12: 677848, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484177

RESUMO

Future precision medicine requires further clarifying the mechanisms of inflammation in the severe endotypes of chronic airway diseases such as asthma and chronic rhinosinusitis (CRS). The presence of neutrophils in the airways is often associated with severe airway inflammation, while their precise contribution to the severe inflammation is largely unknown. We aimed to study the role of neutrophils in BALB/c and C57BL/6 mice exposed to Alternaria alternata (Alt). The mice were exposed to Alt extract for twelve hours or ten days to induce allergic airway inflammation. C57BL/6 mice exposed to Alt responded with eosinophilic infiltration and the characteristic IL-5 upregulation. In contrast, the inflammatory response to Alt extract in BALB/c mice was characterized by a neutrophilic response, high levels of G-CSF, and elastase in the lungs. The lack of neutrophils affected the processing of IL-33 in BALB/c mice, as was demonstrated by depletion of neutrophils through intraperitoneal injections of anti-Ly6G antibody. Our data identifies the key role of neutrophils in airway inflammation through IL-33 cleavage in the Alt-induced airway inflammation in mice, which could potentially underline the different endotypes in human disease.


Assuntos
Alérgenos/imunologia , Alternaria/imunologia , Alternariose/imunologia , Asma/imunologia , Imunidade Inata , Interleucina-33/metabolismo , Neutrófilos/imunologia , Rinite/imunologia , Sinusite/imunologia , Alternariose/microbiologia , Animais , Asma/microbiologia , Modelos Animais de Doenças , Feminino , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Rinite/microbiologia , Sinusite/microbiologia
3.
FASEB J ; 35(10): e21920, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34547141

RESUMO

Autophagy is a self-phagocytic and highly evolutionarily conserved intracellular lysosomal catabolic system, which plays a vital role in a variety of trauma models, including skin wound healing (SWH). However, the roles and potential mechanisms of autophagy in SWH are still controversial. We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP). As expected, we found 3-MA treatment remarkably increased the wound closure rate, combated inflammation response, and mitigated histopathological changes, while RAP delivery aggravated SWH-induced pathological damage. To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied. Herein, treating with 3-MA markedly suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6, promoted that of IL-10, IL-33, and ST2, while RAP administration reverted SWH-induced the up-regulation of these inflammatory cytokines mentioned above. Importantly, Verteporfin administration not only down-regulated the expression levels of YAP, TNF-α, and IL-6 but also up-regulated that of IL-33 and IL-10. Unexpectedly, 3-MA or RAP retreatment did not have any impact on the changes in IL-33 among these inflammatory indicators. Furthermore, elevated expression of IL-33 promoted wound closure and alleviated the pathological damage, whereas, its antagonist Anti-IL-33 treatment overtly reversed the above-mentioned effects of IL-33. Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Autofagia , Interleucina-33/metabolismo , Transdução de Sinais , Pele/metabolismo , Cicatrização , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Sirolimo/farmacologia , Cicatrização/efeitos dos fármacos
4.
Biochem Biophys Res Commun ; 572: 80-85, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34358967

RESUMO

Signal-transducing adaptor protein (STAP)-2 is one of the STAP family adaptor proteins and ubiquitously expressed in a variety types of cells. Although STAP-2 is required for modification of FcεRI signal transduction in mast cells, other involvement of STAP-2 in mast cell functions is unknown, yet. In the present study, we mainly investigated functional roles of STAP-2 in IL-33-induced mast cell activation. In STAP-2-deficient, but not STAP-1-deficient, mast cells, IL-33-induced IL-6 and TNF-α production was significantly decreased compared with that of wild-type mast cells. In addition, STAP-2-deficiency greatly reduced TLR4-mediated mast cell activation and cytokine production. For the mechanisms, STAP-2 directly binds to IKKα after IL-33 stimulation, leading to elevated NF-κB activity. In conclusion, STAP-2, but not STAP-1, participates in IL-33-induced mast cells activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Interleucina-33/metabolismo , Mastócitos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Células Cultivadas , Citocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
5.
J Immunol ; 207(5): 1456-1467, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380650

RESUMO

Cancer immunotherapy has shown great promise as a new standard therapeutic strategy against cancer. However, the response rate and survival benefit remain unsatisfactory because most current approaches, such as the use of immune checkpoint inhibitors, depend on spontaneous antitumor immune responses. One possibility for improving the efficacy of immunotherapy is to promote antitumor immunity using adjuvants or specific cytokines actively. IL-33 has been a candidate for such cytokine therapies, but it remains unclear how and in which situations IL-33 exerts antitumor immune effects. In this study, we demonstrate the potent antitumor effects of IL-33 using syngeneic mouse models, which included marked inhibition of tumor growth and upregulation of IFN-γ production by tumor-infiltrating CD8+ T cells. Of note, IL-33 induced dendritic cells to express semaphorin 4A (Sema4A), and the absence of Sema4A abolished the antitumor activity of IL-33, indicating that Sema4A is intrinsically required for the antitumor effects of IL-33 in mice. Collectively, these results not only present IL-33 and Sema4A as potential therapeutic targets but also shed light on the potential use of Sema4A as a biomarker for dendritic cell activation status, which has great value in various fields of cancer research, including vaccine development.


Assuntos
Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/imunologia , Interleucina-33/metabolismo , Semaforinas/metabolismo , Animais , Biomarcadores/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Semaforinas/genética
6.
Molecules ; 26(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34443554

RESUMO

Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease with complex pathogenesis associated with cytokine dysregulation. Macrophage migration inhibitory factor (MIF) plays a role in systemic inflammation and joint destruction in RA and could be associated with the secretion of other immune-modulatory cytokines such as IL-25, IL-31, and IL-33. For the above, our main aim was to evaluate the IL-25, IL-31, and IL-33 secretion from recombinant human MIF (rhMIF)-stimulated peripheral blood mononuclear cells (PBMC) of RA patients. The rhMIF and lipopolysaccharide (LPS) plus rhMIF stimuli promote the secretion of IL-25, IL-31, and IL-33 (p < 0.05) from PBMC of RA patients. The study groups, the different stimuli, and the interaction between both showed a statistically significant effect on the secretion of IL-25 (p < 0.05) and IL-31 (p < 0.01). The study of the effect of the RA patient treatments and their interaction with the effect of stimuli did not show an interaction between them. In conclusion, our study generates new evidence for the role of MIF in the secretion of IL-25, IL-31, and IL-33 and its immunomodulatory effect on RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Interleucina-17/metabolismo , Interleucina-33/metabolismo , Interleucinas/metabolismo , Oxirredutases Intramoleculares/metabolismo , Leucócitos Mononucleares/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Adulto , Feminino , Humanos , Imunomodulação/efeitos dos fármacos , Oxirredutases Intramoleculares/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/farmacologia
7.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445530

RESUMO

Inflammation is a major contributor to the development and progression of atherosclerosis. Interleukin (IL)-33 and IL-37, members of the IL-1 family, modulate inflammation, with IL-33 having a pro-inflammatory effect and IL-37 having anti-inflammatory properties. IL-37 is constitutively expressed at low levels but upregulated in inflammatory contexts. The aim of this study was to evaluate the effect of vitamin D on the expression of IL-33, IL-37, macrophages, and caspase-1 in the neointimal tissue of coronary artery in Yucatan microswine with vitamin D deficient, sufficient, and supplemented status. The intimal injury was induced by balloon angioplasty and stenting in the coronary artery, and tissues were harvested after 6 months. The expression of various proteins of interest was evaluated by immunostaining. Increased expression of IL-33 and IL-37 in the neointimal tissue of the vitamin D deficient, as compared to the sufficient and supplemented microswine, as revealed by histological evaluation and semi-quantitative analysis, suggested the immunomodulatory effect of vitamin D on the expression of IL-33 and IL-37. The minimal expression or absence of IL-33 and IL-37 expression in stented arteries is suggestive of an attenuated inflammatory response in stented arteries, compared to balloon angioplasty. The decreased IL-33 expression in the sufficient and supplemented microswine could be a potential mechanism for controlling the inflammatory process and neointima formation leading to attenuated luminal narrowing of the coronary artery. Overall, these results support supplementation of vitamin D to attenuate inflammation, neointima formation, and restenosis.


Assuntos
Angioplastia Coronária com Balão/métodos , Doença da Artéria Coronariana/imunologia , Hiperlipidemias/fisiopatologia , Interleucina-1/metabolismo , Interleucina-33/metabolismo , Neointima/imunologia , Stents , Vitamina D/metabolismo , Animais , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/terapia , Suplementos Nutricionais , Imunomodulação , Neointima/patologia , Neointima/terapia , Suínos
9.
Cell Immunol ; 366: 104395, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34198027

RESUMO

Although contributions of IL-33 to pulmonary diseases, including asthma, have been well documented, the complexity of such regulation warrants additional exploration. To better understand the involvement of IL-33, we used a murine asthma surrogate based on sensitisation and challenge with dust mite extract in the presence/absence of IL-33. Murine models were established with Dermatophagoides farinae (Der f) to establish (1) the effect of co-administered rmIL-33; (2) the effect of prior glucocorticoid intervention; (3) the effect of IL-33 on challenge with sub-threshold dosage Der f. The effects of rmIL-33 on bone marrow-derived dendritic cells were explored in vitro. Mice challenged with Der f combined with IL-33 compared with diluent control evinced significantly more airways inflammation and local cytokine production which was less sensitive to inhibition by dexamethasone. IL-33 also induced airways hyperresponsiveness, eosinophilic inflammation and cytokine production in lung tissues of animals exposed to sub-threshold dosage of Der f. In vitro, IL-33-stimulated DCs showed a significantly elevated capacity to stimulate CD4+ T cell proliferation and cytokine production and were also significantly more resistant to dexamethasone-induced apoptosis. Our data suggest that IL-33 reduces the threshold for allergen-induced inflammation of the airways in acorticosteroid-resistant fashion possibly in part through acting on DCs, a phenomenon which may be relevant to the development of severe, corticosteroid-resistant airways obstruction in human asthmatic patients.


Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Inflamação/imunologia , Interleucina-33/metabolismo , Sistema Respiratório/imunologia , Animais , Antialérgicos/uso terapêutico , Antígenos de Dermatophagoides/imunologia , Asma/tratamento farmacológico , Diferenciação Celular , Células Cultivadas , Dermatophagoides farinae , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos , Feminino , Humanos , Inflamação/tratamento farmacológico , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C
10.
Front Immunol ; 12: 636240, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234771

RESUMO

CD8 positive, tissue resident memory T cells (TRM) are a specialized subset of CD8 memory T cells that surveil tissues and provide critical first-line protection against tumors and pathogen re-infection. Recently, much effort has been dedicated to understanding the function, phenotype and development of TRM. A myriad of signals is involved in the development and maintenance of resident memory T cells in tissue. Much of the initial research focused on the roles tissue-derived signals play in the development of TRM, including TGFß and IL-33 which are critical for the upregulation of CD69 and CD103. However, more recent data suggest further roles for antigenic and pro-inflammatory cytokines. This review will focus on the interplay of pro-inflammatory, tissue and antigenic signals in the establishment of resident memory T cells.


Assuntos
Antígenos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Memória Imunológica , Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucinas/metabolismo , Animais , Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Interleucina-33/imunologia , Interleucina-33/metabolismo , Interleucinas/imunologia , Fenótipo , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
11.
PLoS Negl Trop Dis ; 15(7): e0009639, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34324507

RESUMO

Toxocariasis is a neglected disease that affects people around the world. Humans become infected by accidental ingestion of eggs containing Toxocara canis infective larvae, which upon reaching the intestine, hatch, penetrate the mucosa and migrate to various tissues such as liver, lungs and brain. Studies have indicated that Th2 response is the main immune defense mechanism against toxocariasis, however, there are still few studies related to this response, mainly the IL-33/ST2 pathway. Some studies have reported an increase in IL-33 during helminth infections, including T. canis. By binding to its ST2 receptor, IL-33 stimulating the Th2 polarized immune cell and cytokine responses. Thus, we aimed to investigate the role of the IL-33/ST2 pathway in the context of T. canis larval migration and the immunological and pathophysiological aspects of the infection in the liver, lungs and brain from Wild-Type (WT) BALB/c background and genetically deficient mice for the ST2 receptor (ST2-/-). The most important findings revealed that the IL-33/ST2 pathway is involved in eosinophilia, hepatic and cerebral parasitic burden, and induces the formation of granulomas related to tissue damage and pulmonary dysfunction. However, ST2-/- mice, the immune response was skewed to Th1/Th17 type than Th2, that enhanced the control of parasite burden related to IgG2a levels, tissue macrophages infiltration and reduced lung dysfunction. Collectively, our results demonstrate that the Th2 immune response triggered by IL-33/ST2 pathway mediates susceptibility to T. canis, related to parasitic burden, eosinophilia and granuloma formation in which consequently contributes to tissue inflammation and injury.


Assuntos
Eosinófilos/fisiologia , Inflamação/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , Toxocara canis , Toxocaríase/imunologia , Animais , Feminino , Regulação da Expressão Gênica , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Th2/fisiologia , Toxocaríase/patologia
12.
Cells ; 10(6)2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199843

RESUMO

BACKGROUND: Lipopolysaccharide (LPS) of Helicobacter pylori (Hp) bacteria causes disintegration of gastric tissue cells in vitro. It has been suggested that interleukin (IL)-33 is involved in healing gastric injury. AIM: To elucidate whether Hp LPS affects regeneration of gastric barrier initiated by IL-33. METHODS: Primary gastric epithelial cells or fibroblasts from Caviae porcellus were transfected with siRNA IL-33. Such cells, not exposed or treated with LPS Hp, were sub-cultured in the medium with or without exogenous IL-33. Then cell migration was assessed in conjunction with oxidative stress and apoptosis, activation of extracellular signal-regulated kinase (Erk), production of collagen I and soluble ST2 (IL-33 decoy). RESULTS: Control cells not treated with LPS Hp migrated in the presence of IL-33. The pro-regenerative activity of IL-33 was related to stimulation of cells to collagen I production. Wound healing by cells exposed to LPS Hp was inhibited even in the presence of IL-33. This could be due to increased oxidative stress and apoptosis in conjunction with Erk activation, sST2 elevation and modulation of collagen I production. CONCLUSIONS: The recovery of gastric barrier cells during Hp infection potentially can be affected due to downregulation of pro-regenerative activity of IL-33 by LPS Hp.


Assuntos
Células Epiteliais/metabolismo , Fibroblastos/metabolismo , Mucosa Gástrica/fisiologia , Helicobacter pylori/química , Interleucina-33/metabolismo , Lipopolissacarídeos/farmacologia , Regeneração/efeitos dos fármacos , Animais , Cobaias , Lipopolissacarídeos/química
13.
Taiwan J Obstet Gynecol ; 60(4): 658-664, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34247803

RESUMO

OBJECTIVE: Endometriosis is an estrogen-dependent, benign, and chronic gynecological disorder occurring in women of reproductive age. Although the pathogenesis of endometriosis is poorly understood, implantation theory indicates that viable endometrial cells shed from the endometrium into the pelvic peritoneum or ovaries, possibly through retrograde menstruation, and then reattach, invade, and damage other tissues. Interleukin (IL)-33, a new member of the IL-1 superfamily, is mainly upregulated by stromal cells following proinflammatory stimulation. Matrix metalloproteinases (MMPs) are involved in the degradation and reconstruction of the extracellular matrix. MMP-9 participates in the pathogenesis of endometriosis by promoting the invasion of endometriotic cells. This study investigated the effect of IL-33 on the cell invasion ability of and MMP-9 expression in human stromal cells derived from ovarian endometrioma (hOVEN-SCs). MATERIALS AND METHODS: We isolated hOVEN-SCs from human ovarian endometrioma. Gene expression was analyzed using the Illumina Human WG-6 v2 Expression BeadChips microarray platform and through reverse transcription-polymerase chain reaction. Cell migration and invasion were examined by performing the transwell chamber assay. RESULTS: We found that 17ß-estradiol could increase the expression of IL-33 and ST2 through the estrogen receptor pathway in hOVEN-SCs. Moreover, IL-33 upregulated MMP-9 expression in and enhanced the invasion ability of hOVEN-SCs through the ST2/MAPK signaling pathway. Our results showed that MMP-9 expression was essential for IL-33-induced cell invasion. CONCLUSION: Our main finding is that 17ß-estradiol could increase IL-33 expression through the estrogen receptor pathway and activate MMP-9 expression in and invasion ability of hOVEN-SCs through the IL-33/ST2/MAPK signaling pathway. The results of this study and further related studies may provide new strategies for the prevention and treatment of endometriosis.


Assuntos
Endometriose/genética , Endométrio/citologia , Interleucina-33/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Células Estromais/fisiologia , Movimento Celular/genética , Células Cultivadas , Estradiol/metabolismo , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Ovário/citologia
14.
Immunology ; 164(3): 541-554, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34142370

RESUMO

IL-33 and ATP are alarmins, which are released upon damage of cellular barriers or are actively secreted upon cell stress. Due to high-density expression of the IL-33 receptor T1/ST2 (IL-33R), and the ATP receptor P2X7, mast cells (MCs) are one of the first highly sensitive sentinels recognizing released IL-33 or ATP in damaged peripheral tissues. Whereas IL-33 induces the MyD88-dependent activation of the TAK1-IKK2-NF-κB signalling, ATP induces the Ca2+ -dependent activation of NFAT. Thereby, each signal alone only induces a moderate production of pro-inflammatory cytokines and lipid mediators (LMs). However, MCs, which simultaneously sense (co-sensing) IL-33 and ATP, display an enhanced and prolonged activation of the TAK1-IKK2-NF-κB signalling pathway. This resulted in a massive production of pro-inflammatory cytokines such as IL-2, IL-4, IL-6 and GM-CSF as well as of arachidonic acid-derived cyclooxygenase (COX)-mediated pro-inflammatory prostaglandins (PGs) and thromboxanes (TXs), hallmarks of strong MC activation. Collectively, these data show that co-sensing of ATP and IL-33 results in hyperactivation of MCs, which resembles to MC activation induced by IgE-mediated crosslinking of the FcεRI. Therefore, the IL-33/IL-33R and/or the ATP/P2X7 signalling axis are attractive targets for therapeutical intervention of diseases associated with the loss of integrity of cellular barriers such as allergic and infectious respiratory reactions.


Assuntos
Trifosfato de Adenosina/metabolismo , Hipersensibilidade/imunologia , Interleucina-33/metabolismo , Mastócitos/imunologia , Animais , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Degranulação Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Eicosanoides/metabolismo , Humanos , Hipersensibilidade/tratamento farmacológico , Proteína 1 Semelhante a Receptor de Interleucina-1/antagonistas & inibidores , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/antagonistas & inibidores , Lipidômica , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Cultura Primária de Células , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
15.
Exp Cell Res ; 405(2): 112705, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34166678

RESUMO

The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients' serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.


Assuntos
Aloenxertos/imunologia , Rejeição de Enxerto/imunologia , Interleucina-33/metabolismo , Transplante de Rim , Adulto , Anticorpos/farmacologia , Biomarcadores/análise , Feminino , Humanos , Rim/imunologia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo/métodos
16.
Front Immunol ; 12: 654626, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079543

RESUMO

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is involved in various diseases. IL-33 exerts its effects via its heterodimeric receptor complex, which comprises suppression of tumorigenicity 2 (ST2) and the IL-1 receptor accessory protein (IL-1RAP). Increasing evidence has demonstrated that IL-33/ST2 signaling plays diverse but crucial roles in the homeostasis of the central nervous system (CNS) and the pathogenesis of CNS diseases, including neurodegenerative diseases, cerebrovascular diseases, infection, trauma, and ischemic stroke. In the current review, we focus on the functional roles and cellular signaling mechanisms of IL-33 in the CNS and evaluate the potential for diagnostic and therapeutic applications.


Assuntos
Doenças do Sistema Nervoso Central/etiologia , Doenças do Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/metabolismo , Interleucina-33/metabolismo , Animais , Biomarcadores , Doenças do Sistema Nervoso Central/diagnóstico , Doenças do Sistema Nervoso Central/terapia , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Transdução de Sinais
17.
Cells ; 10(6)2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073755

RESUMO

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13-STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver.


Assuntos
Tecido Adiposo/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Interleucina-33/metabolismo , Animais , Expressão Gênica/fisiologia , Interleucina-4/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , PPAR alfa/metabolismo , Fator de Transcrição STAT6/metabolismo
18.
Front Immunol ; 12: 687192, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093589

RESUMO

Dysregulated fatty acid metabolism is clinically associated with eosinophilic allergic diseases, including severe asthma and chronic rhinosinusitis. This study aimed to demonstrate the role of 12/15-lipoxygenase (12/15-LOX) in interleukin (IL)-33-induced eosinophilic airway inflammation; to this end, we used 12/15-LOX-deficient mice, which displayed augmented IL-33-induced lung inflammation, characterized by an increased number of infiltrated eosinophils and group 2 innate lymphoid cells (ILC2s) in the airway. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics revealed that the levels of a series of 12/15-LOX-derived metabolites were significantly decreased, and application of 14(S)-hydroxy docosahexaenoic acid (HDoHE), a major 12/15-LOX-derived product, suppressed IL-33-mediated eosinophilic inflammation in 12/15-LOX-deficient mice. Using bioactive lipid screening, we found that 14(S)-HDoHE and 10(S),17(S)-diHDoHE markedly attenuated ILC2 proliferation and cytokine production at micromolar concentration in vitro. In addition, maresin 1 (MaR1) and resolvin D1 (RvD1), 12/15-LOX-derived specialized proresolving mediators (SPMs), inhibited cytokine production of ILC2s at nanomolar concentration. These findings demonstrate the protective role of endogenous 12/15-LOX-derived lipid mediators in controlling ILC2-mediated eosinophilic airway inflammation and related diseases. Thus, 12/15-LOX-derived lipid mediators may represent a potential therapeutic strategy for ameliorating airway inflammation-associated conditions.


Assuntos
Araquidonato 12-Lipoxigenase/imunologia , Araquidonato 15-Lipoxigenase/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Imunidade Inata/imunologia , Interleucina-33/metabolismo , Linfócitos/imunologia , Pneumonia/imunologia , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/genética , Cromatografia Líquida , Interleucina-33/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/metabolismo , Espectrometria de Massas em Tandem
19.
Sci Rep ; 11(1): 13037, 2021 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-34158522

RESUMO

Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagy pathway is required for resolution of MM by eliminating excess non-secreted intracellular mucin granules. We found increased intracellular levels of mucins Muc5ac and Muc5b in mice deficient in autophagy regulatory protein, Atg16L1, and that this difference was not due to defects in the known baseline or stimulated mucin secretion pathways. Instead, we found that, in mucous secretory cells, Lc3/Lamp1 vesicles colocalized with mucin granules particularly adjacent to the nucleus, suggesting that some granules were being eliminated in the autophagy pathway rather than secreted. Using a mouse model of MM resolution, we found increased lysosomal proteolytic activity that peaked in the days after mucin production began to decline. In purified lysosomal fractions, Atg16L1-deficient mice had reduced proteolytic degradation of Lc3 and Sqstm1 and persistent accumulation of mucin granules associated with impaired resolution of mucous metaplasia. In normal and COPD derived human airway epithelial cells (AECs), activation of autophagy by mTOR inhibition led to a reduction of intracellular mucin granules in AECs. Our findings indicate that during peak and resolution phases of MM, autophagy activity rather than secretion is required for elimination of some remaining mucin granules. Manipulation of autophagy activation offers a therapeutic target to speed resolution of MM in airway disease exacerbations.


Assuntos
Autofagia , Pulmão/metabolismo , Pulmão/patologia , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Muco/metabolismo , Animais , Proteínas Relacionadas à Autofagia/deficiência , Proteínas Relacionadas à Autofagia/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Feminino , Humanos , Inflamação/patologia , Interleucina-33/metabolismo , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Masculino , Metaplasia , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Serina-Treonina Quinases TOR/metabolismo
20.
Nat Commun ; 12(1): 2538, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33953160

RESUMO

Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.


Assuntos
Imunidade Inata/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Neoplasias/terapia , PPAR gama/metabolismo , Animais , Asma , Citocinas/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Hipersensibilidade , Imunoterapia , Linfócitos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Neoplasias/patologia , PPAR gama/genética
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