RESUMEN
IL-1α and IL-1ß (in this article referred to as IL-1) play important roles in host defense against infection and inflammatory diseases. IL-1R1 is the receptor for IL-1, and IL-1R2 is suggested to be a decoy receptor, because it lacks the signal-transducing TIR domain in the cytoplasmic part. However, the roles of IL-1R2 in health and disease remain largely unknown. In this study, we generated EGFP-knock-in Il1r2(-/-) mice and showed that they were highly susceptible to collagen-induced arthritis, an animal model for rheumatoid arthritis in which the expression of IL-1R2 is augmented in inflammatory joints. Il1r2 was highly expressed in neutrophils but had only low expression in other cells, including monocytes and macrophages. Ab production and T cell responses against type II collagen were normal in Il1r2(-/-) mice. Despite the high expression in neutrophils, no effects of Il1r2 deficiency were observed; however, we found that production of inflammatory mediators in response to IL-1 was greatly enhanced in Il1r2(-/-) macrophages. These results suggest that IL-1R2 is an important regulator of arthritis by acting specifically on macrophages as a decoy receptor for IL-1.
Asunto(s)
Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Interleucina-1/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Receptores Tipo II de Interleucina-1/metabolismo , Transducción de Señal , Animales , Formación de Anticuerpos , Artritis Experimental/genética , Artritis Experimental/patología , Citocinas/biosíntesis , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Expresión Génica , Marcación de Gen , Sitios Genéticos , Predisposición Genética a la Enfermedad , Mediadores de Inflamación/metabolismo , Interleucina-1/farmacología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/metabolismo , Especificidad de Órganos , Fenotipo , Receptores Tipo II de Interleucina-1/deficiencia , Receptores Tipo II de Interleucina-1/genética , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor containing a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosinebased inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. Previously, we showed that Dcir(/) mice spontaneously develop autoimmune diseases such as enthesitis and sialadenitis due to excess expansion of dendritic cells (DCs), suggesting that DCIR is critically important for the homeostasis of the immune system. In this report, we analyzed the role of DCIR in the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis. We found that EAE was exacerbated in Dcir(/) mice associated with severe demyelination of the spinal cords. The number of infiltrated CD11c(+) DCs and CD4(+) T cells into spinal cords was increased in Dcir(/) mice. Recall proliferative response of lymph node cells was higher in Dcir(/) mice compared with wild-type mice. These observations suggest that DCIR is an important negative regulator of the immune system, and Dcir(/) mice should be useful for analyzing the roles of DCIR in an array of autoimmune diseases.