CARD9 is an immune adaptor protein in myeloid cells that is involved in C-type lectin signaling and antifungal immunity. CARD9 is implicated in autoimmune and inflammatory-related diseases, such as rheumatoid arthritis, IgA nephropathy, ankylosing spondylitis, and inflammatory bowel disease (IBD). Given that Lyn-deficient (Lyn-/-) mice are susceptible to both autoimmunity and IBD, we investigated the immunological role of CARD9 in the development of these diseases using the Lyn-/- mouse model. We found that genetic deletion of CARD9 was sufficient to reduce the development of both spontaneous autoimmune disease as well as DSS- or IL-10 deficiency-associated colitis in Lyn-/- mice. Mechanistically, CARD9 was a vital component of the Lyn-mediated regulation of Toll-like receptor (TLR2 and TLR4) signaling in dendritic cells, but not in macrophages. In the absence of Lyn, signaling through a CD11b-Syk-PKCδ-CARD9 pathway was amplified, leading to increased TLR-induced production of inflammatory cytokines. Dendritic cell-specific deletion of CARD9 reversed the development of autoimmune and experimental colitis observed in dendritic cell-specific, Lyn-deficient mice. These findings suggest that targeting CARD9 may suppress the development of colitis and autoimmunity by reducing dendritic cell-driven inflammation.

中文翻译：

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CARD9介导树突状细胞诱导的Lyn缺乏相关的自身免疫和炎症性疾病的发展。

CARD9是髓样细胞中的一种免疫衔接蛋白，参与C型凝集素信号传导和抗真菌免疫。CARD9与自身免疫和炎症相关疾病有关，例如类风湿关节炎，IgA肾病，强直性脊柱炎和炎症性肠病（IBD）。鉴于Lyn缺陷（Lyn-/-）小鼠对自身免疫和IBD均敏感，因此我们使用Lyn-/-小鼠模型研究了CARD9在这些疾病发展中的免疫学作用。我们发现CARD9的基因缺失足以减少Lyn-/-小鼠中自发性自身免疫性疾病以及DSS-或IL-10缺乏相关的结肠炎的发展。从机制上讲，CARD9是树突状细胞而非巨噬细胞中Lyn介导的Toll样受体（TLR2和TLR4）信号转导的重要组成部分。在没有Lyn的情况下，通过CD11b-Syk-PKCδ-CARD9途径的信号传导被放大，导致TLR诱导的炎性细胞因子产生增加。树突状细胞特异性缺失的CARD9逆转了在树突状细胞特异性Lyn缺陷小鼠中观察到的自身免疫和实验性结肠炎的发展。这些发现表明，靶向CARD9可以通过减少树突状细胞驱动的炎症来抑制结肠炎和自身免疫性疾病的发展。