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1.
Nat Commun ; 12(1): 805, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547295

RESUMO

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17-IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Disbiose/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interferon gama/imunologia , Interleucinas/imunologia , Fagócitos/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/imunologia , Modelos Animais de Doenças , Disbiose/genética , Disbiose/microbiologia , Disbiose/patologia , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/microbiologia , Doença Enxerto-Hospedeiro/patologia , Interferon gama/deficiência , Interferon gama/genética , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas a Pancreatite/genética , Proteínas Associadas a Pancreatite/imunologia , Fagócitos/citologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores , Irradiação Corporal Total
2.
Chemosphere ; 262: 128009, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182144

RESUMO

Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of individuals in subsequent generations. Bisphenol S (BPS) has been widely used as a substitute for various plastic materials due to the limited application of Bisphenol A (BPA) which is an endocrine disruptor. However, the lack of efficient evaluation of BPS leaves doubts about the relevant substitute of BPA. Few studies of transgenerational inheritance have examined the effects of environmental exposures to endocrine disruptors on the immune system. In this study, we analyzed the transgenerational effects of BPS on intestinal inflammation and its consequence in metabolism. In this study, only F0 pregnant mice were exposed to BPS (1.5 µg/kg bw/day) from gestational day 0 until weaning of offspring. In this work, both F1 and F2 male offspring developed an inflammatory response in the ileum and colon at adulthood after F0 mothers were exposed to BPS; this phenomenon disappeared in F3. This inflammatory response in F1 male offspring is associated with a significant decrease of blood cholesterol without modification of metabolic status. Further, in F3 offspring male, the decrease of gut inflammatory response is associated with a decrease of fat weight and with an increase of blood glucose and cholesterol level. A sex-specific profile is observed in female offspring. We also observed that early life exposure to BPS was associated with strong abnormal intestinal immune status. The study presented here demonstrates that the immune system, like other organ systems, is vulnerable to transgenerational effects caused by environmental exposures.


Assuntos
Citocinas/análise , Disruptores Endócrinos/toxicidade , Intestinos/imunologia , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Sulfonas/toxicidade , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Fezes/química , Feminino , Inflamação , Intestinos/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
3.
PLoS Pathog ; 16(12): e1009121, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351862

RESUMO

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


Assuntos
Interleucina-33/imunologia , Interleucina-9/imunologia , Enteropatias Parasitárias/imunologia , Linfócitos/imunologia , Mastócitos/imunologia , Estrongiloidíase/imunologia , Animais , Imunidade Inata/imunologia , Intestinos/imunologia , Intestinos/parasitologia , Camundongos , Strongyloides ratti/imunologia
4.
J Insect Sci ; 20(6)2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33347588

RESUMO

Peritrophic matrix/membrane (PM) critically prevents the midgut of insects from external invasion by microbes. The proteins in the peritrophic membrane are its major structural components. Additionally, they determine the formation and function of this membrane. However, the role of PM proteins in immune regulation is unclear. Herein, we isolated a novel PM protein (MdPM-17) from Musca domestica larvae. Further, the function of MdPM-17 in regulating host innate immunity was identified. Results showed that the cDNA of MdPM-17 full is 635 bp in length. Moreover, it consists of a 477-bp open reading frame encoding 158 amino acid residues. These amino acid residues are composed of two Chitin-binding type-2 domain (ChtBD2) and 19 amino acids as a signal peptide. Moreover, tissue distribution analysis indicates that MdPM-17 was enriched expressed in midgut, and moderate levels in the fat body, foregut, and malpighian tubule. Notably, MdPM-17 recombinant protein showed high chitin-binding capacity, thus belongs to the Class III PM protein group. MdPM-17 protein silencing via RNA interference resulted in the expression of antimicrobial peptide (defensin, cecropins, and diptericin) genes, and this occurred after oral inoculation with exogenous microbes Escherichia coli (Enterobacteriales:Enterobacteriaceae), Staphylococcus aureus (Bacillales:Staphylococcaceae), and Candida albicans (Endomycetales:Saccharomycetaceae)). Therefore, all the antimicrobial peptide (AMP) gene expression levels are high in MdPM-17-depleted larvae during microbial infection compared to controls. Consequently, these findings indicate that MdPM-17 protein is associated with the antibacterial response from the housefly.


Assuntos
Moscas Domésticas/imunologia , Proteínas de Insetos/isolamento & purificação , Intestinos/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Perfilação da Expressão Gênica , Genes de Insetos , Moscas Domésticas/genética , Moscas Domésticas/metabolismo , Imunidade Inata/fisiologia , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Larva/imunologia , Larva/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Interferência de RNA
5.
Environ Health ; 19(1): 93, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32867778

RESUMO

BACKGROUND: Bisphenol A (BPA), one of the highest-volume chemicals produced worldwide, has been identified as an endocrine disruptor. Many peer-reviewing studies have reported adverse effects of low dose BPA exposure, particularly during perinatal period (gestation and/or lactation). We previously demonstrated that perinatal oral exposure to BPA (via gavage of mothers during gestation and lactation) has long-term consequences on immune response and intestinal barrier functions. Due to its adverse effects on several developmental and physiological processes, BPA was removed from consumer products and replaced by chemical substitutes such as BPS or BPF, that are structurally similar and not well studied compare to BPA. Here, we aimed to compare perinatal oral exposure to these bisphenols (BPs) at two doses (5 and 50 µg/kg of body weight (BW)/day (d)) on immune response at intestinal and systemic levels in female offspring mice at adulthood (Post Natal Day PND70). METHODS: Pregnant female mice were orally exposed to BPA, BPS or BPF at 5 or 50 µg/kg BW/d from 15th day of gravidity to weaning of pups at Post-Natal Day (PND) 21. Humoral and cellular immune responses of adult offspring (PND70) were analysed at intestinal and systemic levels. RESULTS: In female offspring, perinatal oral BP exposure led to adverse effects on intestinal and systemic immune response that were dependant of the BP nature (A, S or F) and dose of exposure. Stronger impacts were observed with BPS at the dose of 5 µg/kg BW/d on inflammatory markers in feces associated with an increase of anti-E. coli IgG in plasma. BPA and BPF exposure induced prominent changes at low dose in offspring mice, in term of intestinal and systemic immune responses, provoking an intestinal and systemic Th1/Th17 inflammation. CONCLUSION: These findings provide, for the first time, results of long-time consequences of BPA, S and F perinatal exposure by oral route on immune response in offspring mice. This work warns that it is mandatory to consider immune markers and dose exposure in risk assessment associated to new BPA's alternatives.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Disruptores Endócrinos/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Fenóis/efeitos adversos , Sulfonas/efeitos adversos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Lactação/efeitos dos fármacos , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Gravidez/efeitos dos fármacos
7.
Proc Natl Acad Sci U S A ; 117(38): 23782-23793, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32907944

RESUMO

Human noroviruses (HuNoVs) are the leading cause of viral gastroenteritis worldwide; yet currently, no vaccines or FDA-approved antiviral drugs are available to counter these pathogens. To understand HuNoV biology and the epithelial response to infection, we performed transcriptomic analyses, RT-qPCR, CRISPR-Cas9 modification of human intestinal enteroid (HIE) cultures, and functional studies with two virus strains (a pandemic GII.4 and a bile acid-dependent GII.3 strain). We identified a predominant type III interferon (IFN)-mediated innate response to HuNoV infection. Replication of both strains is sensitive to exogenous addition of IFNs, suggesting the potential of IFNs as therapeutics. To obtain insight into IFN pathway genes that play a role in the antiviral response to HuNoVs, we developed knockout (KO) HIE lines for IFN alpha and lambda receptors and the signaling molecules, MAVS, STAT1, and STAT2 An unexpected differential response of enhanced replication and virus spread was observed for GII.3, but not the globally dominant GII.4 HuNoV in STAT1-knockout HIEs compared to parental HIEs. These results indicate cellular IFN responses restrict GII.3 but not GII.4 replication. The strain-specific sensitivities of innate responses against HuNoV replication provide one explanation for why GII.4 infections are more widespread and highlight strain specificity as an important factor in HuNoV biology. Genetically modified HIEs for innate immune genes are useful tools for studying immune responses to viral or microbial pathogens.


Assuntos
Infecções por Caliciviridae , Interações Hospedeiro-Patógeno/imunologia , Interferons , Intestinos , Norovirus , Sistemas CRISPR-Cas , Infecções por Caliciviridae/imunologia , Infecções por Caliciviridae/virologia , Humanos , Interferons/genética , Interferons/metabolismo , Intestinos/imunologia , Intestinos/virologia , Modelos Biológicos , Norovirus/genética , Norovirus/imunologia , Norovirus/patogenicidade , Organoides/imunologia , Organoides/virologia , Análise de Sequência de RNA , Transcriptoma/genética , Replicação Viral
8.
Proc Natl Acad Sci U S A ; 117(29): 17166-17176, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632016

RESUMO

Signaling of 17ß-estradiol (estrogen) through its two nuclear receptors, α and ß (ERα, ERß), is an important mechanism of transcriptional regulation. Although ERs are broadly expressed by cells of the immune system, the mechanisms by which they modulate immune responses remain poorly understood. ERß-specific signaling is reduced in patients with chronic inflammatory diseases, including systemic lupus erythematosus and inflammatory bowel disease, and our previous work suggests that dysregulation of ERß-specific signaling contributes to enhanced intestinal inflammation in female SAMP/YitFC mice, a spontaneous model of Crohn's disease-like ileitis. The present study builds on these prior observations to identify a nonredundant, immunoprotective role for ERß-specific signaling in TGF-ß-dependent regulatory T cell (Treg) differentiation. Using a strain of congenic SAMP mice engineered to lack global expression of ERß, we observed dramatic, female-specific exacerbation of intestinal inflammation accompanied by significant reductions in intestinal Treg frequency and function. Impaired Treg suppression in the absence of ERß was associated with aberrant overexpression of Tsc22d3 (GILZ), a glucocorticoid-responsive transcription factor not normally expressed in mature Tregs, and ex vivo data reveal that forced overexpression of GILZ in mature Tregs inhibits their suppressive function. Collectively, our findings identify a pathway of estrogen-mediated immune regulation in the intestine, whereby homeostatic expression of ERß normally functions to limit Treg-specific expression of GILZ, thereby maintaining effective immune suppression. Our data suggest that transcriptional cross-talk between glucocorticoid and steroid sex hormone signaling represents an important and understudied regulatory node in chronic inflammatory disease.


Assuntos
Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Inflamação/imunologia , Intestinos/imunologia , Transdução de Sinais/fisiologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Animais , Doença de Crohn/imunologia , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Feminino , Glucocorticoides/metabolismo , Humanos , Ileíte/patologia , Doenças Inflamatórias Intestinais/imunologia , Intestinos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
9.
Science ; 369(6500)2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32646971

RESUMO

The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in a tissue- and organ-specific manner during homeostasis and in multiple disease processes. This Review discusses recent advances to understand previously unidentified functions of adult mammalian lymphatic vessels, including immunosurveillance and immunomodulation upon pathogen invasion, transport of dietary fat, drainage of cerebrospinal fluid and aqueous humor, possible contributions toward neurodegenerative and neuroinflammatory diseases, and response to anticancer therapies.


Assuntos
Vigilância Imunológica , Vasos Linfáticos/imunologia , Animais , Sistema Nervoso Central/imunologia , Infecções do Sistema Nervoso Central/imunologia , Líquido Cefalorraquidiano/imunologia , Encefalite/imunologia , Homeostase/imunologia , Humanos , Intestinos/imunologia , Vasos Linfáticos/microbiologia , Camundongos , Neoplasias/imunologia , Doenças Neurodegenerativas/imunologia
10.
Exp Parasitol ; 216: 107945, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32615133

RESUMO

Despite decades of investigation to clarify protective mechanisms of anticoccidial responses, one crucial field is neglected, that is, protective memory responses in primed birds. Protective memory immunity is critical for host resistance to reinfection and is the basis of modern vaccinology, especially in developing successful subunit vaccines. There are important differences between the immune responses induced by infections and antigens delivered either as killed, recombinant proteins or as live, replicating vector vaccines or as DNA vaccines. Animals immunized with these vaccines may fail to develop protective memory immunity, and is still naïve to Eimeria infection. This may explain why limited success is achieved in developing next-generation anticoccidial vaccines. In this review, we try to decipher the protective memory responses against Eimeria infection, assess immune responses elicited by various anticoccidial vaccine candidates, and propose possible approaches to develop rational vaccines that can induce a protective memory response to chicken coccidiosis.


Assuntos
Galinhas/parasitologia , Coccidiose/veterinária , Eimeria/imunologia , Memória Imunológica/fisiologia , Doenças das Aves Domésticas/imunologia , Vacinas Protozoárias , Animais , Galinhas/imunologia , Coccidiose/imunologia , Coccidiose/prevenção & controle , Intestinos/imunologia , Intestinos/parasitologia , Doenças das Aves Domésticas/prevenção & controle , Vacinas Protozoárias/imunologia , Recidiva , Vacinação/veterinária , Vacinas de Subunidades/imunologia
11.
Nat Commun ; 11(1): 3334, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620760

RESUMO

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.


Assuntos
Homeostase/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Intestinos/imunologia , Células Th17/imunologia , Animais , Plasticidade Celular/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
12.
Anim Sci J ; 91(1): e13433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671948

RESUMO

This study investigated the protective effects of probiotic on heat stress-induced intestinal injury and inflammatory response in broilers. A total of 180 male broilers were randomly allocated to three treatments with four replicates each from 22 to 42 days of age. The broilers were either raised under thermoneutral (TN) conditions (23 ± 1°C) or subjected to cyclic heat stress (28-35-28°C for 12 hr daily). The broilers kept at TN conditions were fed a basal diet, and those exposed to heat stress were fed basal diets supplemented with or without probiotic at a dose of 1.5 × 108  cfu/kg. Compared with the TN group, heat stress decreased (p < .05) the growth performance, reduced (p < .05) villus height and villus height: crypt depth ratio in intestinal mucosa, increased (p < .05) serum levels of D-lactic acid on day 28 and endotoxin, TNF-α and IL-6 on day 42, and decreased (p < .05) serum IL-10 content on day 42. Dietary supplementation of probiotic reversed (p < .05) all these changes except for the growth performance in heat-stressed broilers. In conclusion, dietary inclusion of probiotic could improve intestinal morphology and barrier function, alleviate inflammatory response, but exert no ameliorative effect on growth performance of broilers under cyclic heat stress.


Assuntos
Suplementos Nutricionais , Resposta ao Choque Térmico , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Intestinos/imunologia , Probióticos/administração & dosagem , Animais , Galinhas , Dieta , Temperatura Alta , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Interleucina-6/sangue , Intestinos/anatomia & histologia , Masculino , Probióticos/farmacologia , Fator de Necrose Tumoral alfa/sangue
13.
Exp Parasitol ; 215: 107901, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525007

RESUMO

Eimeria tenella (E. tenella) has caused severe economic loss in chicken production, especially after the forbidden use of antibiotics in feed. Considering the drug resistant problem caused by misuse of chemoprophylaxis and live oocyst vaccines can affect the productivity of chickens, also it has the risk to reversion of virulence, the development of efficacious, convenient and safe vaccines is still deeply needed. In this study, the EtMic2 protein of E. tenella was anchored on the surface of Lactobacillus plantarum (L. plantarum) NC8 strain. The newly constructed strain was then used to immunize chickens, followed by E. tenella challenge. The results demonstrated that the recombinant strain could provide efficient protection against E. tenella, shown by increased relative body weight gains, percentages of CD4+ and CD8+ T cells, humoral immune response and inflammatory cytokines. In addition, decreased cecum lesion scores and fecal oocyst shedding were also observed during the experiment. In conclusion, this study proves the possibility to use L. plantarum as a vessel to deliver protective antigen to protect chickens against coccidiosis.


Assuntos
Antígeno 12E7/imunologia , Galinhas/parasitologia , Coccidiose/veterinária , Eimeria tenella/imunologia , Doenças das Aves Domésticas/prevenção & controle , Vacinas Protozoárias , Animais , Antígenos de Protozoários/imunologia , Ceco/parasitologia , Coccidiose/economia , Coccidiose/parasitologia , Coccidiose/prevenção & controle , Eimeria tenella/química , Citometria de Fluxo/veterinária , Técnica Indireta de Fluorescência para Anticorpo/veterinária , Imunoglobulina A Secretora/biossíntese , Imunoglobulina G/sangue , Interferon gama/sangue , Interleucina-2/sangue , Intestinos/imunologia , Lactobacillus plantarum/genética , Lactobacillus plantarum/imunologia , Doenças das Aves Domésticas/economia , Doenças das Aves Domésticas/parasitologia , Distribuição Aleatória , Vacinas Sintéticas
14.
Nature ; 585(7826): 591-596, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32526765

RESUMO

Recent clinical and experimental evidence has evoked the concept of the gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1-4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.


Assuntos
Encéfalo/citologia , Intestinos/citologia , Intestinos/inervação , Fígado/citologia , Fígado/inervação , Neurônios/fisiologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Vias Aferentes , Animais , Células Apresentadoras de Antígenos/imunologia , Colite/imunologia , Colite/metabolismo , Colite/patologia , Homeostase , Humanos , Intestinos/imunologia , Masculino , Camundongos , Ratos , Receptores Muscarínicos/metabolismo , Baço/citologia , Baço/imunologia , Nervo Vago/fisiologia
15.
Food Chem ; 324: 126840, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32344339

RESUMO

Functional foods have created an open environment for the development of new solutions to health-related issues. In celiac disease, there is still no therapeutic alternative other than the observance of a gluten-free diet. In this context, we developed a wheat flour enriched in l-theanine aimed to be a potential alternative to the gluten-free diet. Through microbial transglutaminase-catalysed transamidation of gluten proteins using ethylamine as amine nucleophile, substantial amounts of glutamine residues were converted in theanine residues. Furthermore, using T-cell lines generated from intestinal biopsy specimens of celiac disease patients, this treatment showed the potential to strongly reduce the ability of gluten proteins to stimulate a T-cell-mediated immune response. From a rheological point of view, the functionality of gluten was retained. Considering L-theanine's evidence-based health benefits, a novel functional food is presented here and for celiac disease can be a path towards the development of an alternative to the gluten-free diet.


Assuntos
Doença Celíaca/imunologia , Farinha , Glutamatos/química , Glutens/química , Linfócitos T/imunologia , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Suplementos Nutricionais , Elasticidade , Etilaminas/metabolismo , Alimento Funcional , Glutens/metabolismo , Humanos , Intestinos/citologia , Intestinos/imunologia , Transglutaminases/metabolismo , Triticum
16.
PLoS Pathog ; 16(4): e1008498, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32282854

RESUMO

We investigated the role of the inflammasome effector caspases-1 and -11 during Salmonella enterica serovar Typhimurium infection of murine intestinal epithelial cells (IECs). Salmonella burdens were significantly greater in the intestines of caspase-1/11 deficient (Casp1/11-/-), Casp1-/- and Casp11-/- mice, as compared to wildtype mice. To determine if this reflected IEC-intrinsic inflammasomes, enteroid monolayers were derived and infected with Salmonella. Casp11-/- and wildtype monolayers responded similarly, whereas Casp1-/- and Casp1/11-/- monolayers carried significantly increased intracellular burdens, concomitant with marked decreases in IEC shedding and death. Pretreatment with IFN-γ to mimic inflammation increased caspase-11 levels and IEC death, and reduced Salmonella burdens in Casp1-/- monolayers, while high intracellular burdens and limited cell shedding persisted in Casp1/11-/- monolayers. Thus caspase-1 regulates inflammasome responses in IECs at baseline, while proinflammatory activation of IECs reveals a compensatory role for caspase-11. These results demonstrate the importance of IEC-intrinsic canonical and non-canonical inflammasomes in host defense against Salmonella.


Assuntos
Caspase 1/imunologia , Caspases Iniciadoras/imunologia , Inflamassomos/imunologia , Intestinos/enzimologia , Intestinos/imunologia , Infecções por Salmonella/enzimologia , Salmonella typhimurium/imunologia , Animais , Células Epiteliais/enzimologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Imunidade nas Mucosas , Inflamassomos/metabolismo , Interferon gama/imunologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Lipopolissacarídeos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Salmonella/imunologia , Salmonella typhimurium/patogenicidade
17.
PLoS One ; 15(4): e0231222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251446

RESUMO

IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Interleucina-17/metabolismo , Intestinos/imunologia , Células Th1/citologia , Animais , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/citologia , Células CACO-2 , Proliferação de Células , Microbioma Gastrointestinal , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Ribossômico 16S/metabolismo
18.
Dig Dis Sci ; 65(5): 1299-1306, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32124197

RESUMO

Intestinal fibrosis is a common outcome of inflammatory bowel diseases (IBDs), becoming clinically apparent in 40% of patients with Crohn's disease and 5% of those with ulcerative colitis. Effective pharmacological treatments aimed at controlling or reversing fibrosis progression are unavailable. Fibrosis is characterized by an excessive local accumulation of extracellular matrix proteins (mainly collagen), as a result of their increased production by activated myofibroblasts and/or their reduced degradation by specific matrix metalloproteinases. Initiation and progression of fibrosis are modulated by several pro- and anti-fibrogenic molecules. In recent years, the cytokine interleukin-17 (IL-17) has been integrated into the pathogenesis of fibrosis, although its precise contribution to IBD, and especially to its related intestinal fibrosis, remains controversial. Several data suggest both a pro-inflammatory and pro-fibrotic action and a protective function of the Th17/IL-17 immune response. A recent study has demonstrated that the treatment with anti-IL-17 antibody significantly alleviated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colorectal fibrosis in mice by down-regulating the expression of collagen 3 and several pro-fibrogenic cytokines. Here, we describe and discuss the possible involvement of the Th17/IL-17 immune response in the initiation ad progression of intestinal fibrosis.


Assuntos
Imunidade Adaptativa , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/imunologia , Intestinos/patologia , Células Th17/imunologia , Animais , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Citocinas/imunologia , Fibrose , Humanos , Doenças Inflamatórias Intestinais/patologia , Intestinos/imunologia , Miofibroblastos/imunologia
19.
Poult Sci ; 99(3): 1311-1319, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32111307

RESUMO

This study was conducted to evaluate the effects and combinational effects of Bacillus subtilis (BS) and montmorillonite (MMT) on laying performance, gut mucosal oxidation status, and intestinal immunological and physical barrier functions of laying hens. Three hundred sixty laying hens (29-week-old) were randomly assigned to a 2 × 2 factorial arrangement of treatments (n = 6) for 10 wk as follows: (1) basal diet; (2) the basal diet plus 5 × 108 cfu BS/kg; (3) the basal diet plus 0.5 g MMT/kg; and (4) the basal diet plus 5 × 108 cfu BS/kg and 0.5 g MMT/kg. Dietary supplementation with BS increased egg production and egg mass, the activities of catalase (CAT) and total superoxide dismutase in the intestinal mucosa, and villus height and villus height-to-crypt depth ratio of the jejunum (P < 0.05) but downregulated the mRNA expression levels of toll-like receptor 4 and myeloid differentiation factor 88 (MyD88) in the duodenum and jejunum, interleukin 1 beta in the duodenum, and nuclear factor kappa B P65 (NF-κB P65) and tumor necrosis factor alpha in the jejunum (P < 0.05). Dietary supplementation with MMT increased egg production and egg mass, the concentration of secretory immunoglobulin A in the duodenum, and the occludin mRNA expression level in the jejunum (P < 0.05) but reduced feed conversion ratio, malondialdehyde concentration in the duodenum and jejunum, and the mRNA expression level of MyD88 in the jejunum (P < 0.05). In addition, there was an interaction effect between BS and MMT supplementation on the CAT activity and the MyD88 mRNA expression level in the duodenum and the mRNA expression level of occludin in the jejunum (P < 0.05). In conclusion, dietary BS and MMT and their combination may improve the intestinal health status of laying hens, which may contribute to the increase in hens' laying performance.


Assuntos
Bacillus subtilis/química , Bentonita/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Bentonita/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais/análise , Intestinos/imunologia , Oxirredução , Probióticos , Distribuição Aleatória , Reprodução
20.
Proc Natl Acad Sci U S A ; 117(15): 8431-8436, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32220957

RESUMO

Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.


Assuntos
Translocação Bacteriana , Epóxido Hidrolases/imunologia , Enteropatias/enzimologia , Intestinos/enzimologia , Obesidade/complicações , Tecido Adiposo/imunologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Fenômenos Fisiológicos Bacterianos , Epóxido Hidrolases/genética , Microbioma Gastrointestinal , Humanos , Enteropatias/etiologia , Enteropatias/imunologia , Enteropatias/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/enzimologia , Obesidade/genética
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