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1.
Immunity ; 51(5): 871-884.e6, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31628054

RESUMEN

Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deficiency of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived interleukin-22 (IL-22) production. This led to impaired gut epithelial function characterized by altered mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 increased IL-22+ CCR6+ ILC3s and influenced ILC3 abundance in colonic lymphoid tissues. Ffar2 agonism differentially activated AKT or ERK signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings suggest that Ffar2 regulates colonic ILC3 proliferation and function, and they identify an ILC3-receptor signaling pathway modulating gut homeostasis and pathogen defense.


Asunto(s)
Inmunidad Innata , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Biomarcadores , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Microbioma Gastrointestinal/inmunología , Expresión Génica , Humanos , Inmunomodulación , Mucosa Intestinal/patología , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt , Receptores de Superficie Celular/agonistas , Factor de Transcripción STAT3/metabolismo
2.
Immunity ; 40(5): 706-19, 2014 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-24792912

RESUMEN

Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.


Asunto(s)
Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Interleucina-10/inmunología , Receptores de Interleucina-10/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Humanos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-10/deficiencia , Receptores de Interleucina-10/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunología
3.
Gastroenterology ; 158(5): 1359-1372.e9, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31917258

RESUMEN

BACKGROUND & AIMS: Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. METHODS: We performed studies with ApcMin/+ mice, ApcMin/+Ffar2-/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas. RESULTS: ApcMin/+Ffar2-/- mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2-/- mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2-/- mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs, than mice not given the agonist. DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production. CONCLUSIONS: Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC.


Asunto(s)
Colitis/patología , Neoplasias del Colon/inmunología , Células Dendríticas/inmunología , Microbioma Gastrointestinal/inmunología , Interleucinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/inmunología , Colitis/inducido químicamente , Colitis/inmunología , Colon/efectos de los fármacos , Colon/microbiología , Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Células Dendríticas/metabolismo , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ácidos Grasos no Esterificados/metabolismo , Femenino , Humanos , Interleucinas/inmunología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Masculino , Ratones , Ratones Noqueados , Permeabilidad , Cultivo Primario de Células , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética
4.
Proc Natl Acad Sci U S A ; 114(1): 142-147, 2017 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-27980034

RESUMEN

Hosts and their microbes have established a sophisticated communication system over many millennia. Within mammalian hosts, this dynamic cross-talk is essential for maintaining intestinal homeostasis. In a genetically susceptible host, dysbiosis of the gut microbiome and dysregulated immune responses are central to the development of inflammatory bowel disease (IBD). Previous surveys of stool from the T-bet-/-Rag2-/- IBD mouse model revealed microbial features that discriminate between health and disease states. Enterobacteriaceae expansion and increased gene abundances for benzoate degradation, two-component systems, and bacterial motility proteins pointed to the potential involvement of a catecholamine-mediated bacterial signaling axis in colitis pathogenesis. Enterobacteriaceae sense and respond to microbiota-generated signals and host-derived catecholamines through the two-component quorum-sensing Escherichia coli regulators B and C (QseBC) system. On signal detection, QseC activates a cascade to induce virulence gene expression. Although a single pathogen has not been identified as a causative agent in IBD, adherent-invasive Escherichia coli (AIEC) have been implicated. Flagellar expression is necessary for the IBD-associated AIEC strain LF82 to establish colonization. Thus, we hypothesized that qseC inactivation could reduce LF82's virulence, and found that an absence of qseC leads to down-regulated flagellar expression and motility in vitro and reduced colonization in vivo. We extend these findings on the potential of QseC-based IBD therapeutics to three preclinical IBD models, wherein we observe that QseC blockade can effectively modulate colitogenic microbiotas to reduce intestinal inflammation. Collectively, our data support a role for QseC-mediated bacterial signaling in IBD pathogenesis and indicate that QseC inhibition may be a useful microbiota-targeted approach for disease management.


Asunto(s)
Colitis/patología , Colitis/terapia , Proteínas de Escherichia coli/antagonistas & inhibidores , Proteínas de Escherichia coli/genética , Escherichia coli/metabolismo , Percepción de Quorum/efectos de los fármacos , Animales , Catecolaminas/metabolismo , Colitis/microbiología , Flagelos/genética , Flagelos/metabolismo , Microbioma Gastrointestinal , Regulación Bacteriana de la Expresión Génica/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Sulfonamidas/farmacología , Virulencia/genética
6.
Gut Microbes ; 13(1): 1987780, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34781821

RESUMEN

The colorectal cancer (CRC)-associated microbiota creates a pro-tumorigenic intestinal milieu and shapes immune responses within the tumor microenvironment. However, how oncomicrobes - like Fusobacterium nucleatum, found in the oral cavity and associated with CRC tissues- affect these distinct aspects of tumorigenesis is difficult to parse. Herein, we found that neonatal inoculation of ApcMin/+ mice with F. nucleatum strain Fn7-1 circumvents technical barriers preventing its intestinal colonization, drives colonic Il17a expression prior to tumor formation, and potentiates intestinal tumorigenesis. Using gnotobiotic mice colonized with a minimal complexity microbiota (the altered Schaedler's flora), we observed that intestinal Fn7-1 colonization increases colonic Th17 cell frequency and their IL-17A and IL-17F expression, along with a concurrent increase in colonic lamina propria Il23p19 expression. As Fn7-1 stably colonizes the intestinal tract in our models, we posited that microbial metabolites, specifically short-chain fatty acids (SCFA) that F. nucleatum abundantly produces in culture and, as we demonstrate, in the intestinal tract, might mediate part of its immunomodulatory effects in vivo. Supporting this hypothesis, we found that Fn7-1 did not alter RORγt+ CD4+T cell frequency in the absence of the SCFA receptor FFAR2. Taken together, our work suggests that F. nucleatum influences intestinal immunity by shaping Th17 responses in an FFAR2-dependent manner, although further studies are necessary to clarify the precise and multifaceted roles of FFAR2. The potential to increase intestinal Th17 responses is shared by another oncomicrobe, enterotoxigenic Bacteroides fragilis, highlighting a conserved pathway that could potentially be targeted to slow oncomicrobe-mediated CRC.


Asunto(s)
Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/microbiología , Fusobacterium nucleatum/fisiología , Interleucina-17/inmunología , Mucosa Intestinal/inmunología , Células Th17/inmunología , Animales , Colon/inmunología , Colon/microbiología , Neoplasias Colorrectales/genética , Femenino , Fusobacterium nucleatum/crecimiento & desarrollo , Microbioma Gastrointestinal , Humanos , Interleucina-17/genética , Mucosa Intestinal/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología
7.
Elife ; 82019 01 22.
Artículo en Inglés | MEDLINE | ID: mdl-30666959

RESUMEN

Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn's disease risk allele ATG16L1 T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of ATG16L1 T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into ATG16L1 T300A knock-in mice. We observed increases in Bacteroides ovatus and Th1 and Th17 cells in ATG16L1 T300A mice. Association of altered Schaedler flora mice with B. ovatus specifically increased Th17 cells selectively in ATG16L1 T300A knock-in mice. Changes occur before disease onset, suggesting that ATG16L1 T300A contributes to dysbiosis and immune infiltration prior to disease symptoms. Our work provides insight for future studies on IBD subtypes, IBD patient treatment and diagnostics.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Enfermedad de Crohn/genética , Enfermedad de Crohn/microbiología , Microbioma Gastrointestinal , Células TH1/citología , Células Th17/citología , Alelos , Animales , Bacteroides , Disbiosis/genética , Disbiosis/microbiología , Trasplante de Microbiota Fecal , Heces/microbiología , Técnicas de Sustitución del Gen , Genotipo , Humanos , Sistema Inmunológico , Ratones , Polimorfismo Genético , Riesgo , Células TH1/microbiología , Células Th17/microbiología
8.
Cell Metab ; 26(1): 8-10, 2017 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-28683297

RESUMEN

Diet can alter the gut microbiota and shift its production of metabolites, which affect systemic immune function. In Nature Immunology, Mariño et al. (2017) explore diet-gut microbiome interactions in type 1 diabetes and identify mechanisms by which short-chain fatty acids prevent T cell destruction of pancreatic ß-cells.


Asunto(s)
Diabetes Mellitus Tipo 1/microbiología , Fibras de la Dieta/metabolismo , Ácidos Grasos Volátiles/metabolismo , Microbioma Gastrointestinal , Células Secretoras de Insulina/patología , Linfocitos T/patología , Animales , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Humanos , Células Secretoras de Insulina/metabolismo , Linfocitos T/metabolismo
9.
Science ; 351(6279): 1329-33, 2016 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-26847546

RESUMEN

The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.


Asunto(s)
Células Quimiorreceptoras/inmunología , Parasitosis Intestinales/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Microbiota/inmunología , Canales Catiónicos TRPM/inmunología , Animales , Quinasas Similares a Doblecortina , Eosinófilos/inmunología , Células Caliciformes/inmunología , Helmintiasis/inmunología , Helmintiasis/parasitología , Helmintos/inmunología , Inmunidad Mucosa , Interleucina-13/inmunología , Interleucina-17/inmunología , Parasitosis Intestinales/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas Serina-Treonina Quinasas/inmunología , Infecciones por Protozoos/inmunología , Infecciones por Protozoos/parasitología , Transducción de Señal , Gusto , Transducina/genética , Transducina/inmunología , Tritrichomonas/inmunología
10.
Cell Rep ; 12(2): 244-57, 2015 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-26146082

RESUMEN

Our study reveals a non-canonical role for CCL2 in modulating non-macrophage, myeloid-derived suppressor cells (MDSCs) and shaping a tumor-permissive microenvironment during colon cancer development. We found that intratumoral CCL2 levels increased in patients with colitis-associated colorectal cancer (CRC), adenocarcinomas, and adenomas. Deletion of CCL2 blocked progression from dysplasia to adenocarcinoma and reduced the number of colonic MDSCs in a spontaneous mouse model of colitis-associated CRC. In a transplantable mouse model of adenocarcinoma and an APC-driven adenoma model, CCL2 fostered MDSC accumulation in evolving colonic tumors and enhanced polymorphonuclear (PMN)-MDSC immunosuppressive features. Mechanistically, CCL2 regulated T cell suppression of PMN-MDSCs in a STAT3-mediated manner. Furthermore, CCL2 neutralization decreased tumor numbers and MDSC accumulation and function. Collectively, our experiments support that perturbing CCL2 and targeting MDSCs may afford therapeutic opportunities for colon cancer interception and prevention.


Asunto(s)
Adenocarcinoma/patología , Quimiocina CCL2/metabolismo , Neoplasias del Colon/patología , Adenocarcinoma/etiología , Adenocarcinoma/metabolismo , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Transformación Celular Neoplásica , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/genética , Colitis/complicaciones , Colitis/patología , Neoplasias del Colon/etiología , Neoplasias del Colon/metabolismo , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células Mieloides/citología , Células Mieloides/metabolismo , Neutrófilos/citología , Neutrófilos/metabolismo , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética
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