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/inmunologíaRESUMEN
The two specialized C. elegans distal tip cells (DTCs) provide an in vivo model system for the study of developmentally regulated cell migration. We identified cacn-1/cactin, a well-conserved, novel regulator of cell migration in a genome-wide RNAi screen for regulators of DTC migration. RNAi depletion experiments and analysis of the hypomorphic allele cacn-1(tm3126) indicate that CACN-1 is required during DTC migration for proper pathfinding and for cessation of DTC migration at the end of larval morphogenesis. Strong expression of CACN-1 in the DTCs, and data from cell-specific RNAi depletion experiments, suggest that CACN-1 is required cell-autonomously to control DTC migration. Importantly, genetic interaction data with Rac GTPase activators and effectors suggest that CACN-1 acts specifically to inhibit the mig-2/Rac pathway, and in parallel to ced-10/Rac, to control DTC pathfinding.
Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/citología , Proteínas Portadoras/metabolismo , Movimiento Celular , Proteínas de Drosophila/metabolismo , Proteínas de Unión al GTP rac/metabolismo , Animales , Caenorhabditis elegans/embriología , Proteínas de Caenorhabditis elegans/genética , Proteínas Portadoras/genética , Proteínas de Drosophila/genética , Gónadas/embriología , Proteínas de Unión al GTP rac/genéticaRESUMEN
BACKGROUND: The chemokine CCL25, and its receptor CCR9, constitute a unique chemokine/receptor pair, which regulates trafficking of T lymphocytes to the small intestine under physiological conditions and is an attractive target for small bowel Crohn's disease drug development. We have previously shown that CCL25/CCR9 interactions regulate the recovery from acute dextran sulfate sodium-induced colonic inflammation. In this study, we explored whether these interactions also regulate chronic colitis development in 2 independent murine models of experimental colitis. METHODS: Histological flow cytometry and qPCR analyses were performed to evaluate the role of CL25 and CCR9 in chronic colonic inflammation induced by serial exposures to dextran sulfate sodium salts or by adoptive transfer of CD45RB(hi) CD4(+) T cell into lymphopenic mice devoid of CCL25/CCR9 interactions. RESULTS: Chronic dextran sulfate sodium exposure results in exacerbated colitis in mice deficient for either CCR9 or CCL25 when compared with wild-type control mice. Although CCR9-deficient T cells traffic to the colon and induce severe colitis similar to wild-type T cells in the CD45RB transfer model, naive wild-type T cells induce more severe disease in recipient animals devoid of CCL25 expression. CONCLUSIONS: CCL25/CCR9 interactions are required for modulating protection against large intestinal inflammation in 2 models of chronic colitis. These data may have implications for the potential effects of disrupting CCL25/CCR9 interactions in humans in the setting of intestinal disorders including inflammatory bowel disease.