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1.
J Sci Food Agric ; 102(1): 434-444, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34143895

RESUMO

BACKGROUND: The incidence of inflammatory bowel disease (IBD) continues to increase worldwide. Multiple factors, including diet, loss of the intestinal barrier function, and imbalance of the immune system can cause IBD. A balanced diet is important for maintaining a healthy bowel and preventing IBD from occurring. The effects of probiotic Lactobacillus gasseri-fermented Maillard reaction products (MRPs) prepared by reacting whey protein with galactose on anti-inflammation and intestinal homeostasis were investigated in this study, which compared MPRs and probiotics separately. RESULTS: In an animal colitis model induced by 2% dextran sulfate sodium (DSS), FWG administration alleviated colon length loss and maintained intestinal immune system homeostasis as reflected by down-regulated interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α output, and metallopeptidase-9, and epithelial barrier balance as reflected by up-regulated occludin, E-cadherin, and zonula occludens-1 production in the colon. Furthermore, the expression of splenic cytokines such as IL-6, TNF-α, and IL-10 was up-regulated in the FWG-treated mice in a comparable amount to the control group to ensure the balance of immune responses. CONCLUSION: This study showed that the use of FWG protects the intestines from colitis caused by DSS and maintains immune balance. FWG increased antioxidant enzyme activity, increased intestinal permeability, and regulated the balance of pro- and anti-inflammatory cytokines in the intestines and spleen. Continued intake of FWG can alleviate IBD symptoms through the preservation of mucosal immune responses, epithelial junction and homeostasis through the regulated splenic cytokines. © 2021 Society of Chemical Industry.


Assuntos
Colite/tratamento farmacológico , Produtos Finais de Glicação Avançada/administração & dosagem , Lactobacillus gasseri/metabolismo , Probióticos/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Colite/induzido quimicamente , Colite/imunologia , Colite/fisiopatologia , Colo/efeitos dos fármacos , Colo/imunologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Galactose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Homeostase/efeitos dos fármacos , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Junções Íntimas/genética , Junções Íntimas/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteínas do Soro do Leite/metabolismo
2.
Nat Immunol ; 22(11): 1440-1451, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34686860

RESUMO

Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.


Assuntos
Colite/enzimologia , Colo/enzimologia , Citotoxicidade Imunológica , Complexo II de Transporte de Elétrons/metabolismo , Células Epiteliais/enzimologia , Doença Enxerto-Hospedeiro/enzimologia , Mucosa Intestinal/enzimologia , Mitocôndrias/enzimologia , Linfócitos T/imunologia , Animais , Estudos de Casos e Controles , Comunicação Celular , Células Cultivadas , Colite/genética , Colite/imunologia , Colite/patologia , Colo/imunologia , Colo/ultraestrutura , Modelos Animais de Doenças , Complexo II de Transporte de Elétrons/genética , Células Epiteliais/imunologia , Células Epiteliais/ultraestrutura , Feminino , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/ultraestrutura , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/imunologia , Mitocôndrias/ultraestrutura , Fosforilação Oxidativa , Ácido Succínico/metabolismo , Linfócitos T/metabolismo
3.
J Immunol ; 207(10): 2456-2464, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34615735

RESUMO

Lactoferrin (LF) is known to possess anti-inflammatory activity, although its mechanisms of action are not well-understood. The present study asked whether LF affects the commitment of inducible regulatory T cells (Tregs). LF substantially promoted Foxp3 expression by mouse activated CD4+T cells, and this activity was further enhanced by TGF-ß1. Interestingly, blocking TGF-ß with anti-TGF-ß Ab completely abolished LF-induced Foxp3 expression. However, no significant amount of soluble TGF-ß was released by LF-stimulated T cells, suggesting that membrane TGF-ß (mTGF-ß) is associated. Subsequently, it was found that LF binds to TGF-ß receptor III, which induces reactive oxygen species production and diminishes the expression of mTGF-ß-bound latency-associated peptide, leading to the activation of mTGF-ß. It was followed by phosphorylation of Smad3 and enhanced Foxp3 expression. These results suggest that LF induces Foxp3+ Tregs through TGF-ß receptor III/reactive oxygen species-mediated mTGF-ß activation, triggering canonical Smad3-dependent signaling. Finally, we found that the suppressive activity of LF-induced Tregs is facilitated mainly by CD39/CD73-induced adenosine generation and that this suppressor activity alleviates inflammatory bowel disease.


Assuntos
Lactoferrina/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Colite/imunologia , Colite/metabolismo , Lactoferrina/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos BALB C , Receptores de Fatores de Crescimento Transformadores beta/efeitos dos fármacos , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
4.
J Immunol ; 207(8): 2027-2038, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34518282

RESUMO

RORγt is the master transcription factor for the Th17 cells. Paradoxically, in the intestine, RORγt is coexpressed in peripherally induced regulatory T cells (pTregs) together with Foxp3, the master transcription factor for Tregs. Unexpectedly, by an unknown mechanism, colonic RORγt+ Tregs show an enhanced suppressor function and prevent intestinal inflammation more efficiently than RORγt-nonexpressing pTregs. Although studies have elucidated the function of RORγt in Th17 cells, how RORγt regulates pTreg function is not understood. In our attempt to understand the role of RORγt in controlling Treg function, we discovered a RORγt-driven pathway that modulates the regulatory (suppressor) function of colonic Tregs. We found that RORγt plays an essential role in maintaining Foxp3 expression. RORγt-deficient Tregs failed to sustain Foxp3 expression with concomitant upregulation of T-bet and IFN-γ expressions. During colitis induced by adoptive transfer of CD45RBhi cells in Rag1 -/- mice, RORγt-deficient colonic Tregs transitioned to a Th1-like effector phenotype and lost their suppressor function, leading to severe colitis with significant mortality. Accordingly, Foxp3-expressing, RORγt-deficient Tregs showed impaired therapeutic efficacy in ameliorating colitis that is not due to their reduced survival. Moreover, using the Treg-specific RORγt and T-bet double-deficient gene knockout mouse, we demonstrate that deletion of T-bet from RORγt-deficient Tregs restored Foxp3 expression and suppression function as well as prevented onset of severe colitis. Mechanistically, our study suggests that RORγt-mediated repression of T-bet is critical to regulating the immunosuppressive function of colonic Tregs during the inflammatory condition.


Assuntos
Colite/imunologia , Colo/imunologia , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Células Cultivadas , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Proteínas com Domínio T/genética
5.
Nat Commun ; 12(1): 4907, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389726

RESUMO

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Homeostase/imunologia , Mucosa Intestinal/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Homeostase/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
6.
Front Immunol ; 12: 618365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434187

RESUMO

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara -/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.


Assuntos
Atorvastatina/farmacologia , Colite/tratamento farmacológico , PPAR alfa/imunologia , Animais , Colite/induzido quimicamente , Colite/genética , Colite/imunologia , Sulfato de Dextrana/toxicidade , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Knockout , PPAR alfa/genética , Células Th17/imunologia , Células Th2/imunologia
7.
Front Immunol ; 12: 669787, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335571

RESUMO

The hallmarks of inflammatory bowel disease are mucosal damage and ulceration, which are known to be high-risk conditions for the development of colorectal cancer. Recently, interleukin (IL)-33 and its receptor ST2 have emerged as critical modulators in inflammatory disorders. Even though several studies highlight the IL-33/ST2 pathway as a key factor in colitis, a detailed mode of action remains elusive. Therefore, we investigated the role of IL-33 during intestinal inflammation and its potential as a novel therapeutic target in colitis. Interestingly, the expression of IL-33, but not its receptor ST2, was significantly increased in biopsies from the inflamed colon of IBD patients compared to non-inflamed colonic tissue. Accordingly, in a mouse model of Dextran Sulfate Sodium (DSS) induced colitis, the secretion of IL-33 significantly accelerated in the colon. Induction of DSS colitis in ST2-/- mice displayed an aggravated colon pathology, which suggested a favorable role of the IL 33/ST2 pathway during colitis. Indeed, injecting rmIL-33 into mice suffering from acute DSS colitis, strongly abrogated epithelial damage, pro-inflammatory cytokine secretion, and loss of barrier integrity, while it induced a strong increase of Th2 associated cytokines (IL-13/IL-5) in the colon. This effect was accompanied by the accumulation of regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) in the colon. Depletion of Foxp3+ Tregs during IL-33 treatment in DSS colitis ameliorated the positive effect on the intestinal pathology. Finally, IL-33 expanded ILC2s, which were adoptively transferred to DSS treated mice, significantly reduced colonic inflammation compared to DSS control mice. In summary, our results emphasize that the IL-33/ST2 pathway plays a crucial protective role in colitis by modulating ILC2 and Treg numbers.


Assuntos
Anti-Inflamatórios/farmacologia , Proliferação de Células/efeitos dos fármacos , Colite/prevenção & controle , Colo/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Interleucina-33/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Transferência Adotiva , Animais , Colite/induzido quimicamente , Colite/imunologia , Colite/metabolismo , Colo/imunologia , Colo/metabolismo , Colo/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Células Caliciformes/imunologia , Células Caliciformes/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
8.
J Immunol ; 207(6): 1530-1544, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34408011

RESUMO

MHC class I (MHC-I)-restricted CD4+ T cells have long been discovered in the natural repertoire of healthy humans as well as patients with autoimmune diseases or cancer, but the exact origin of these cells remains to be fully characterized. In mouse models, mature peripheral CD8+ T cells have the potential to convert to CD4+ T cells in the mesenteric lymph nodes. This conversion can produce a unique population of MHC-I-restricted CD4+ T cells including Foxp3+ regulatory T cells termed MHC-I-restricted CD4+Foxp3+ T (CI-Treg) cells. In this study we examined the cellular and molecular elements that promote CD8-to-CD4 lineage conversion and the development of CI-Treg cells in mice. Using adoptive transfer and bone marrow chimera experiments, we found that the differentiation of CI-Treg cells was driven by lymph node stromal cell (LNSC)-intrinsic MHC-II expression as opposed to transcytosis of MHC-II from bone marrow-derived APCs. The lineage conversion was accompanied by Runx3 versus ThPOK transcriptional switch. This finding of a new role for LNSCs in vivo led us to develop an efficient tissue culture method using LNSCs to generate and expand CI-Treg cells in vitro. CI-Treg cells expanded in vitro with LNSCs effectively suppressed inflammatory tissue damage caused by pathogenic CD4+ T cells in mouse models of colitis. This study identified a novel role of MHC-II expressed by LNSCs in immune regulation and the potential utilization of LNSCs to generate novel subsets of immune regulatory cells for therapeutic applications.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/genética , Colite/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfonodos/imunologia , Transdução de Sinais/genética , Células Estromais/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva/métodos , Animais , Células Apresentadoras de Antígenos/imunologia , Linhagem da Célula/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
Science ; 373(6558)2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34446580

RESUMO

The immune system has evolved in the face of microbial exposure. How maternal infection experienced at distinct developmental stages shapes the offspring immune system remains poorly understood. Here, we show that during pregnancy, maternally restricted infection can have permanent and tissue-specific impacts on offspring immunity. Mechanistically, maternal interleukin-6 produced in response to infection can directly impose epigenetic changes on fetal intestinal epithelial stem cells, leading to long-lasting impacts on intestinal immune homeostasis. As a result, offspring of previously infected dams develop enhanced protective immunity to gut infection and increased inflammation in the context of colitis. Thus, maternal infection can be coopted by the fetus to promote long-term, tissue-specific fitness, a phenomenon that may come at the cost of predisposition to inflammatory disorders.


Assuntos
Colite/imunologia , Imunidade , Interleucina-6/imunologia , Intestinos/imunologia , Complicações Infecciosas na Gravidez/imunologia , Células Th17/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Animais , Candidíase/imunologia , Cromatina/metabolismo , Epigênese Genética , Epigenoma , Feminino , Desenvolvimento Fetal , Microbioma Gastrointestinal/imunologia , Microbioma Gastrointestinal/fisiologia , Interleucina-6/sangue , Interleucina-6/farmacologia , Mucosa Intestinal/citologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/imunologia , Intestinos/embriologia , Intestinos/microbiologia , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Salmonelose Animal/imunologia , Células-Tronco/imunologia , Células-Tronco/fisiologia , Subpopulações de Linfócitos T/imunologia
10.
Molecules ; 26(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199466

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray-Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.


Assuntos
Bactérias/classificação , Produtos Biológicos/administração & dosagem , Colite/tratamento farmacológico , Crocus/química , Sulfato de Dextrana/efeitos adversos , Microbiota/efeitos dos fármacos , Administração Oral , Animais , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Produtos Biológicos/farmacologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Filogenia , Profilaxia Pré-Exposição , Serotonina/metabolismo , Resultado do Tratamento
11.
Sci Rep ; 11(1): 14582, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34272410

RESUMO

Recently the role of Parkinson's disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)-compound increasing PARK7 activity-treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn's disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-ß treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.


Assuntos
Colite/metabolismo , Citocinas/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Proteína Desglicase DJ-1/fisiologia , Adolescente , Animais , Criança , Pré-Escolar , Colite/induzido quimicamente , Colite/imunologia , Colo/metabolismo , Colo/patologia , Citocinas/imunologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica , Células HT29 , Humanos , Peróxido de Hidrogênio , Lactente , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade
12.
Nat Immunol ; 22(8): 969-982, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34312548

RESUMO

The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4+ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg cells and conversion to CD4+ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Linfócitos Intraepiteliais/citologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/imunologia , Colite/imunologia , Colite/prevenção & controle , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/genética , Transcrição Genética/genética
13.
Nature ; 596(7870): 114-118, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34262174

RESUMO

Pathogenic fungi reside in the intestinal microbiota but rarely cause disease. Little is known about the interactions between fungi and the immune system that promote commensalism. Here we investigate the role of adaptive immunity in promoting mutual interactions between fungi and host. We find that potentially pathogenic Candida species induce and are targeted by intestinal immunoglobulin A (IgA) responses. Focused studies on Candida albicans reveal that the pathogenic hyphal morphotype, which is specialized for adhesion and invasion, is preferentially targeted and suppressed by intestinal IgA responses. IgA from mice and humans directly targets hyphal-enriched cell-surface adhesins. Although typically required for pathogenesis, C. albicans hyphae are less fit for gut colonization1,2 and we show that immune selection against hyphae improves the competitive fitness of C. albicans. C. albicans exacerbates intestinal colitis3 and we demonstrate that hyphae and an IgA-targeted adhesin exacerbate intestinal damage. Finally, using a clinically relevant vaccine to induce an adhesin-specific immune response protects mice from C. albicans-associated damage during colitis. Together, our findings show that adaptive immunity suppresses harmful fungal effectors, with benefits to both C. albicans and its host. Thus, IgA uniquely uncouples colonization from pathogenesis in commensal fungi to promote homeostasis.


Assuntos
Imunidade Adaptativa , Candida albicans/imunologia , Candida albicans/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Simbiose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos de Fungos/imunologia , Candida albicans/patogenicidade , Colite/imunologia , Colite/microbiologia , Colite/patologia , Feminino , Vacinas Fúngicas/imunologia , Microbioma Gastrointestinal/imunologia , Humanos , Hifas/imunologia , Imunoglobulina A/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
14.
Nat Commun ; 12(1): 3611, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127673

RESUMO

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, ß-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/ß-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.


Assuntos
Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Polissacarídeos/imunologia , Saccharomyces cerevisiae/metabolismo , beta-Glucanas/imunologia , Animais , Linfócitos T CD4-Positivos , Diferenciação Celular/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Ciclo-Oxigenase 2 , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental , Glucanos , Proteínas de Homeodomínio/genética , Imunidade , Lectinas Tipo C , Mananas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Saccharomyces cerevisiae/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1 , Zimosan , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia
15.
Immunity ; 54(6): 1123-1136.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34107271

RESUMO

Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34-/- mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.


Assuntos
Apoptose/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Lisofosfolipídeos/imunologia , Neutrófilos/imunologia , Receptores de Lisofosfolipídeos/imunologia , Animais , Células Cultivadas , Colite/imunologia , Colo/imunologia , Homeostase/imunologia , Humanos , Interleucinas/imunologia , Mucosa Intestinal/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/imunologia
16.
Front Immunol ; 12: 648341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093536

RESUMO

Behçet's disease (BD) is a multisystem autoinflammatory condition characterized by mucosal ulceration, breakdown of immune privilege sites and vasculitis. A genetic basis for BD has been described in genome-wide and validation studies. Similarly, dysbiosis of oral and gut microbiomes have been associated with BD. This review will describe links between genetic polymorphisms in genes encoding molecules involved in gut biology and changes seen in microbiome studies. A potential decrease in bacterial species producing short chain fatty acids linked to mutations in genes involved in their production suggests a potential therapy for BD.


Assuntos
Síndrome de Behçet/genética , Síndrome de Behçet/microbiologia , Disbiose/genética , Microbioma Gastrointestinal/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Animais , Bactérias/metabolismo , Síndrome de Behçet/imunologia , Butiratos/metabolismo , Butiratos/uso terapêutico , Colite/tratamento farmacológico , Colite/imunologia , Colite/microbiologia , Modelos Animais de Doenças , Disbiose/imunologia , Disbiose/metabolismo , Ácidos Graxos Voláteis/metabolismo , Humanos , Camundongos , Mutação , Resultado do Tratamento
17.
Immunity ; 54(5): 1022-1036.e8, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33932356

RESUMO

The sympathetic nervous system is composed of an endocrine arm, regulating blood adrenaline and noradrenaline, and a local arm, a network of fibers innervating immune organs. Here, we investigated the impact of the local arm of the SNS in an inflammatory response in the colon. Intra-rectal insertion of an optogenetic probe in mice engineered to express channelrhodopsin-2 in tyrosine hydroxylase cells activated colonic sympathetic fibers. In contrast to systemic application of noradrenaline, local activation of sympathetic fibers attenuated experimental colitis and reduced immune cell abundance. Gene expression profiling showed decreased endothelial expression of the adhesion molecule MAdCAM-1 upon optogenetic stimulation; this decrease was sensitive to adrenergic blockers and 6-hydroxydopamine. Antibody blockade of MAdCAM-1 abrogated the optogenetic effect on immune cell extravasation into the colon and the pathology. Thus, sympathetic fibers control colonic inflammation by regulating immune cell extravasation from circulation, a mechanism likely relevant in multiple organs.


Assuntos
Colite/imunologia , Colo/imunologia , Colo/inervação , Organogênese/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Molécula 1 de Adesão Intercelular/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/métodos
18.
Immunity ; 54(6): 1137-1153.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051146

RESUMO

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.


Assuntos
Colite/imunologia , Disbiose/imunologia , Imunidade Inata/imunologia , Proteínas de Membrana/imunologia , Células Mieloides/imunologia , Ubiquitinação/imunologia , Animais , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/imunologia , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia
19.
BMC Cancer ; 21(1): 607, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034704

RESUMO

BACKGROUND: The nuclear phosphatase mitogen-activate protein kinase phosphatase-1 (MKP-1) is a key negative regulator of the innate immune response through the regulation of the biosynthesis of proinflammatory cytokines. In colorectal cancer (CRC), which is induced mainly by chronic inflammation, Mkp-1 overexpression was found in addition to disturbances in Mkp-1 functions, which may play a role in cancer development in different types of tumors. However, the potential molecular mechanisms by which Mkp-1 influences CRC development is not clear. Here, we performed global gene expression profiling of Mkp-1 KO mice using RNA sequencing (RNA-seq) to explore the role of Mkp-1 in CRC progression using transcriptome analysis. METHODS: Azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were used to examine the most dramatic molecular and signaling changes that occur during different phases of CRC development in wild-type mice and Mkp-1 KO mice. Comprehensive bioinformatics analyses were used to elucidate the molecular processes regulated by Mkp-1. Differentially expressed genes (DEGs) were identified and functionally analyzed by Gene Ontology (GO), Kyoto Enrichment of Genes and Genomes (KEGG). Then, protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape software. RESULTS: Persistent DEGs were different in adenoma and carcinoma stage (238 & 251, respectively) and in WT and MKp-1 KO mice (221& 196, respectively). Mkp-1 KO modulated key molecular processes typically activated in cancer, in particular, cell adhesion, ion transport, extracellular matrix organization, response to drug, response to hypoxia, and response to toxic substance. It was obvious that these pathways are closely associated with cancer development and metastasis. From the PPI network analyses, nine hub genes associated with CRC were identified. CONCLUSION: These findings suggest that MKp-1 and its hub genes may play a critical role in cancer development, prognosis, and determining treatment outcomes. We provide clues to build a potential link between Mkp-1 and colitis-associated tumorigenesis and identify areas requiring further investigation.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Associadas a Colite/genética , Colite/complicações , Fosfatase 1 de Especificidade Dupla/metabolismo , Regulação Neoplásica da Expressão Gênica , Animais , Azoximetano/administração & dosagem , Azoximetano/toxicidade , Biomarcadores Tumorais/genética , Carcinogênese/genética , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Neoplasias Associadas a Colite/imunologia , Neoplasias Associadas a Colite/patologia , Biologia Computacional , Sulfato de Dextrana/administração & dosagem , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Fosfatase 1 de Especificidade Dupla/genética , Humanos , Masculino , Camundongos , Camundongos Knockout , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , RNA-Seq , Transdução de Sinais/genética
20.
Front Immunol ; 12: 664998, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995396

RESUMO

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Recent clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. Reports have highlighted the potential use of helminths and their byproducts as potential treatment for IBD. In the current study, we studied the effect of a newborn larvae-specific serine protease from Trichinella spiralis (TsSp) on the host immune and inflammatory responses. A 49-kDa recombinant TsSp (rTsSp) was expressed in Escherichia coli BL21 (DE3) and purified. The cytotoxicity of rTsSp was analyzed. The immune protective effect of rTsSp was studied by using dextran sodium sulfate (DSS)-induced mouse colitis model. The result illustrated that rTsSp has no toxic effects on cells. We further demonstrated that administration of the rTsSp without the additional adjuvant before the induction of DSS-induced colitis reduced the severity of intestinal inflammation and the disease index; it suppressed macrophage infiltration, reduced TNF-α secretion, and induced IL-10 expression. Our findings suggest therapeutic potential of rTsSp on colitis by altering the effect of macrophages. Data also suggest immunotherapy with rTsSp holds promise for use as an additional strategy to positively modulate inflammatory processes involved in IBD.


Assuntos
Colite/prevenção & controle , Proteínas de Helminto/química , Fatores Imunológicos/farmacologia , Serina Proteases/imunologia , Trichinella spiralis/química , Animais , Colite/induzido quimicamente , Colite/imunologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Proteínas de Helminto/isolamento & purificação , Interleucina-10/metabolismo , Larva/fisiologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Trichinella spiralis/isolamento & purificação , Fator de Necrose Tumoral alfa/metabolismo
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