RESUMEN
In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1ß and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3-grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1ß and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell-mediated severe immunopathology in helminthic disease.
Asunto(s)
Moléculas de Adhesión Celular/inmunología , Células Dendríticas/inmunología , Regulación de la Expresión Génica/inmunología , Lectinas Tipo C/inmunología , Receptores de Superficie Celular/inmunología , Schistosoma/inmunología , Esquistosomiasis/inmunología , Células Th17/inmunología , Animales , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Línea Celular , Células Dendríticas/metabolismo , Células Dendríticas/patología , Activación Enzimática/genética , Activación Enzimática/inmunología , Femenino , Regulación de la Expresión Génica/genética , Silenciador del Gen/inmunología , Granuloma/genética , Granuloma/inmunología , Granuloma/patología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Interleucina-23/genética , Interleucina-23/inmunología , Interleucina-23/metabolismo , Lectinas Tipo C/biosíntesis , Lectinas Tipo C/genética , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Endogámicos CBA , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/inmunología , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/inmunología , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/genética , Proteínas Proto-Oncogénicas pp60(c-src)/inmunología , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismo , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Schistosoma/genética , Schistosoma/metabolismo , Esquistosomiasis/genética , Esquistosomiasis/metabolismo , Esquistosomiasis/patología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Células Th17/metabolismo , Células Th17/patologíaRESUMEN
The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1ß and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1ß and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRγ-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs.