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1.
Mucosal Immunol ; 15(4): 629-641, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35501356

RESUMO

The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake.


Assuntos
Neuropeptídeos , Peptídeo Intestinal Vasoativo , Citocinas/metabolismo , Imunidade Inata , Intestinos , Linfócitos , Neuropeptídeos/metabolismo
2.
Science ; 376(6590): eabj3986, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35420957

RESUMO

Gut bacteria influence brain functions and metabolism. We investigated whether this influence can be mediated by direct sensing of bacterial cell wall components by brain neurons. In mice, we found that bacterial peptidoglycan plays a major role in mediating gut-brain communication via the Nod2 receptor. Peptidoglycan-derived muropeptides reach the brain and alter the activity of a subset of brain neurons that express Nod2. Activation of Nod2 in hypothalamic inhibitory neurons is essential for proper appetite and body temperature control, primarily in females. This study identifies a microbe-sensing mechanism that regulates feeding behavior and host metabolism.


Assuntos
Proteína Adaptadora de Sinalização NOD2 , Peptidoglicano , Animais , Apetite , Bactérias/genética , Bactérias/metabolismo , Temperatura Corporal , Camundongos , Neurônios/metabolismo , Proteína Adaptadora de Sinalização NOD2/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Peptidoglicano/metabolismo
3.
Immunity ; 50(5): 1276-1288.e5, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30902637

RESUMO

Microbes colonize all body surfaces at birth and participate in the development of the immune system. In newborn mammals, the intestinal microbiota is first shaped by the dietary and immunological components of milk and then changes upon the introduction of solid food during weaning. Here, we explored the reactivity of the mouse intestinal immune system during the first weeks after birth and into adulthood. At weaning, the intestinal microbiota induced a vigorous immune response-a "weaning reaction"-that was programmed in time. Inhibition of the weaning reaction led to pathological imprinting and increased susceptibility to colitis, allergic inflammation, and cancer later in life. Prevention of this pathological imprinting was associated with the generation of RORγt+ regulatory T cells, which required bacterial and dietary metabolites-short-chain fatty acids and retinoic acid. Thus, the weaning reaction to microbiota is required for immune ontogeny, the perturbation of which leads to increased susceptibility to immunopathologies later in life.


Assuntos
Microbioma Gastrointestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Linfócitos T Reguladores/imunologia , Desmame , Animais , Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/microbiologia , Ácidos Graxos Voláteis/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tretinoína/metabolismo
4.
Nat Metab ; 1(11): 1101-1109, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694861

RESUMO

Epidemiological data reveal an association between obesity and inflammatory bowel disease (IBD). Furthermore, animal models demonstrate that maternal high-fat diet (HFD) and maternal obesity increase susceptibility to IBD in offspring. Here we report that excess calorie intake by neonatal mice, as a consequence of maternal HFD, forced feeding of neonates or low litter competition, leads to an increase during weaning in intestinal permeability, expression of pro-inflammatory cytokines and hydrogen sulfide production by the microbiota. These intestinal changes engage in mutual positive feedback that imprints increased susceptibility to colitis in adults. The pathological imprinting is prevented by the neutralization of IFN-γ and TNF-α or the production of hydrogen sulfide, or by normalization of intestinal permeability during weaning. We propose that excess calorie intake by neonates leads to multiple causally linked perturbations in the intestine that imprint the individual with long-term susceptibility to IBD.


Assuntos
Colite/etiologia , Suscetibilidade a Doenças , Ingestão de Energia , Exposição Materna , Animais , Animais Recém-Nascidos , Feminino , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
5.
Nat Metab ; 1(11): 1169, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32694867

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
J Exp Med ; 215(11): 2936-2954, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30355616

RESUMO

The foodborne pathogen Listeria monocytogenes (Lm) crosses the intestinal villus epithelium via goblet cells (GCs) upon the interaction of Lm surface protein InlA with its receptor E-cadherin. Here, we show that Lm infection accelerates intestinal villus epithelium renewal while decreasing the number of GCs expressing luminally accessible E-cadherin, thereby locking Lm portal of entry. This novel innate immune response to an enteropathogen is triggered by the infection of Peyer's patch CX3CR1+ cells and the ensuing production of IL-23. It requires STAT3 phosphorylation in epithelial cells in response to IL-22 and IL-11 expressed by lamina propria gp38+ stromal cells. Lm-induced IFN-γ signaling and STAT1 phosphorylation in epithelial cells is also critical for Lm-associated intestinal epithelium response. GC depletion also leads to a decrease in colon mucus barrier thickness, thereby increasing host susceptibility to colitis. This study unveils a novel innate immune response to an enteropathogen, which implicates gp38+ stromal cells and locks intestinal villus invasion, but favors colitis.


Assuntos
Colite/imunologia , Mucosa Intestinal/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Glicoproteínas de Membrana/imunologia , Células Mieloides/imunologia , Nódulos Linfáticos Agregados/imunologia , Animais , Colite/genética , Colite/microbiologia , Colite/patologia , Citocinas/genética , Citocinas/imunologia , Imunidade Inata/genética , Imunidade nas Mucosas/genética , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Listeriose/genética , Listeriose/patologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Células Mieloides/microbiologia , Células Mieloides/patologia , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/patologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Células Estromais/imunologia , Células Estromais/microbiologia , Células Estromais/patologia
7.
Proc Natl Acad Sci U S A ; 114(4): E506-E513, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-28074039

RESUMO

The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34+ Gp38+ αSMA- mesenchymal cells closely associated with Lgr5+ IESCs. We demonstrate that CD34+ Gp38+ cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5+ IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34+ Gp38+ cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34+gp38+ cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34+ Gp38+ mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury.


Assuntos
Antígenos CD34/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Nicho de Células-Tronco , Animais , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana , Homeostase , Mucosa Intestinal/citologia , Camundongos Endogâmicos C57BL
8.
PLoS One ; 11(2): e0147871, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26844551

RESUMO

Cerebral Malaria (CM) is associated with a pathogenic T cell response. Mice infected by P. berghei ANKA clone 1.49 (PbA) developing CM (CM+) present an altered PBL TCR repertoire, partly due to recurrently expanded T cell clones, as compared to non-infected and CM- infected mice. To analyse the relationship between repertoire alteration and CM, we performed a kinetic analysis of the TRBV repertoire during the course of the infection until CM-related death in PbA-infected mice. The repertoires of PBL, splenocytes and brain lymphocytes were compared between infected and non-infected mice using a high-throughput CDR3 spectratyping method. We observed a modification of the whole TCR repertoire in the spleen and blood of infected mice, from the fifth and the sixth day post-infection, respectively, while only three TRBV were significantly perturbed in the brain of infected mice. Using multivariate analysis and statistical modelling, we identified a unique TCRß signature discriminating CM+ from CTR mice, enriched during the course of the infection in the spleen and the blood and predicting CM onset. These results highlight a dynamic modification and compartmentalization of the TCR diversity during the course of PbA infection, and provide a novel method to identify disease-associated TCRß signature as diagnostic and prognostic biomarkers.


Assuntos
Variação Genética , Malária Cerebral/genética , Malária Cerebral/parasitologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Animais , Encéfalo/imunologia , Encéfalo/parasitologia , Regiões Determinantes de Complementaridade/genética , Modelos Animais de Doenças , Malária Cerebral/diagnóstico , Malária Cerebral/imunologia , Camundongos , Plasmodium berghei , Prognóstico , Baço/imunologia , Baço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Science ; 349(6251): 989-93, 2015 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-26160380

RESUMO

Changes to the symbiotic microbiota early in life, or the absence of it, can lead to exacerbated type 2 immunity and allergic inflammations. Although it is unclear how the microbiota regulates type 2 immunity, it is a strong inducer of proinflammatory T helper 17 (T(H)17) cells and regulatory T cells (T(regs)) in the intestine. Here, we report that microbiota-induced T(regs) express the nuclear hormone receptor RORγt and differentiate along a pathway that also leads to T(H)17 cells. In the absence of RORγt(+) T(regs), T(H)2-driven defense against helminths is more efficient, whereas T(H)2-associated pathology is exacerbated. Thus, the microbiota regulates type 2 responses through the induction of type 3 RORγt(+) T(regs) and T(H)17 cells and acts as a key factor in balancing immune responses at mucosal surfaces.


Assuntos
Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/microbiologia , Microbiota/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Colite Ulcerativa/imunologia , Colo/imunologia , Colo/microbiologia , Vida Livre de Germes , Homeostase , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Intestinos/imunologia , Camundongos , Modelos Imunológicos , Nematospiroides dubius , Organismos Livres de Patógenos Específicos , Infecções por Strongylida/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th2/imunologia , Vitamina A/metabolismo
10.
Eur J Immunol ; 45(5): 1524-34, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25726757

RESUMO

Analyses of the regulatory T (Treg) cell TCR repertoire should help elucidate the nature and diversity of their cognate antigens and thus how Treg cells protect us from autoimmune diseases. We earlier identified CD44(hi) CD62L(low) activated/memory (am) Treg cells as a Treg-cell subset with a high turnover and possible self-specificity. We now report that amTreg cells are predominantly distributed in lymph nodes (LNs) draining deep tissues. Multivariate analyses of CDR3 spectratyping first revealed that amTreg TCR repertoire is different from that of naïve Treg cells (nTreg cells) and effector T (Teff) cells. Furthermore, in deep- versus superficial LNs, TCR-ß deep sequencing further revealed diversified nTreg-cell and amTreg-cell repertoires, although twofold less diverse than that of Teff cells, and with repertoire richness significantly lower in deep-LN versus superficial-LN Treg cells. Importantly, expanded clonotypes were mostly detected in deep-LN amTreg cells, some accounting for 20% of the repertoire. Strikingly, these clonotypes were absent from nTreg cells, but found at low frequency in Teff cells. Our results, obtained in nonmanipulated mice, indicate different antigenic targets for naïve and amTreg cells and that amTreg cells are self-specific. The data we present are consistent with an instructive component in Treg-cell differentiation.


Assuntos
Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/imunologia , Regiões Determinantes de Complementaridade/genética , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Memória Imunológica , Linfonodos/citologia , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência de DNA , Distribuição Tecidual
11.
Nat Med ; 18(8): 1262-70, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22842476

RESUMO

Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α-positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12(+) cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12(+) cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12(+) cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12(+) cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.


Assuntos
Proteínas ADAM/análise , Cicatriz/patologia , Derme/lesões , Músculo Esquelético/lesões , Miofibroblastos/patologia , Células Estromais/patologia , Proteínas ADAM/deficiência , Proteínas ADAM/genética , Proteína ADAM12 , Doença Aguda , Adipócitos/patologia , Animais , Vasos Sanguíneos/citologia , Linhagem da Célula , Proteínas Cardiotóxicas de Elapídeos/toxicidade , Colágeno/biossíntese , Cruzamentos Genéticos , Derme/metabolismo , Derme/patologia , Orelha Externa/lesões , Orelha Externa/metabolismo , Orelha Externa/patologia , Fibrose , Adjuvante de Freund/toxicidade , Técnicas de Silenciamento de Genes , Genes Reporter , Traumatismos da Perna/metabolismo , Traumatismos da Perna/patologia , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miofibroblastos/metabolismo , Parabiose , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/análise , Organismos Livres de Patógenos Específicos , Células Estromais/metabolismo , Cicatrização
12.
Nat Immunol ; 12(4): 320-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21336274

RESUMO

Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (T(H)17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue-inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to T(H)17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.


Assuntos
Intestinos/imunologia , Tecido Linfoide/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais/imunologia , Imunidade Adaptativa/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Feminino , Citometria de Fluxo , Homeostase/imunologia , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simbiose/imunologia , Fatores de Tempo , Interleucina 22
13.
J Immunol ; 183(7): 4182-6, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19767568

RESUMO

The CD4 coreceptor is mandatory for the differentiation and function of conventional MHC class II-restricted T cells, but little is known about its contribution in regulatory T cells (Tregs). We thus investigated the Treg compartment in mice lacking CD4. CD3+CD8-FoxP3+ cells were readily detected in the periphery of CD4(-/-) mice, where their percentages were even increased as compared with wild-type animals. These cells had a classical CD25+CD152+GITR+ Treg phenotype, were enriched in memory-type Tregs, and displayed a diversified TCR repertoire. Functionally, CD4(-/-) Tregs were equally as suppressive as CD4(+/+) Tregs in vitro as well as in vivo. Hence, the CD4 coreceptor is dispensable for the generation and function of FoxP3+ Tregs. Furthermore, CD3+CD8-FoxP3+ Tregs were also found to develop in the absence of both CD4 and MHC-II molecules, demonstrating that the generation of Tregs can occur independently of MHC-II recognition.


Assuntos
Antígenos CD4/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Complexo CD3/genética , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/biossíntese , Linfócitos T Reguladores/citologia
14.
J Immunol ; 182(9): 5789-99, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19380827

RESUMO

Stromal cells in lymphoid tissues regulate lymphocyte recruitment and survival through the expression of specific chemokines and cytokines. During inflammation, the same signals recruit lymphocytes to the site of injury; however, the "lymphoid" stromal (LS) cells producing these signals remain poorly characterized. We find that mouse inflammatory lesions and tumors develop gp38(+) LS cells, in recapitulation of the development of LS cells early during the ontogeny of lymphoid organs and the intestine, and express a set of genes that promotes the development of lymphocyte-permissive tissues. These gp38(+) LS cells are induced by a robust pathway that requires myeloid cells but not known Toll- or NOD-like receptors, the inflammasome, or adaptive immunity. Parabiosis and inducible genetic cell fate mapping experiments indicate that local precursors, presumably resident fibroblasts rather that circulating precursors, massively proliferate and give rise to LS cells during inflammation. Our results show that LS cells are both programmed during ontogeny and reinduced during inflammation.


Assuntos
Movimento Celular/imunologia , Inflamação/imunologia , Inflamação/patologia , Tecido Linfoide/imunologia , Tecido Linfoide/patologia , Animais , Quimiocinas/biossíntese , Citocinas/biossíntese , Inflamação/embriologia , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Mucosa Intestinal/embriologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leishmania major/imunologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Tecido Linfoide/embriologia , Glicoproteínas de Membrana/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Células Estromais/imunologia , Células Estromais/metabolismo , Células Estromais/patologia
15.
FEBS Lett ; 559(1-3): 89-95, 2004 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-14960313

RESUMO

We have previously shown that HMGA1 enhances the transcriptional activity of promoters containing the estrogen response element (ERE) and increases binding of the estrogen receptor (ER) to ERE. Herein, we have assessed the transcriptional activity and ERE-binding ability of deleted ER fragments in absence or in presence of HMGA1. The HMGA1 protein stimulated binding and transcriptional activity by a factor of about 2-fold compared to the wild-type ER and both the N- and C-terminal ER deleted domains, but had no effect when both domains were deleted. These data show that HMGA1 cooperates with either the N- or the C-terminal transcriptional activation domain of the ER.


Assuntos
Proteína HMGA1a/metabolismo , Receptores de Estrogênio/química , Receptores de Estrogênio/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Receptor alfa de Estrogênio , Proteína HMGA1a/genética , Proteína HMGA1a/fisiologia , Humanos , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Estrogênio/genética , Elementos de Resposta , Deleção de Sequência , Transcrição Gênica , Ativação Transcricional , Transfecção
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