CARD9 mediates dendritic cell-induced development of Lyn deficiency-associated autoimmune and inflammatory diseases

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-PKC-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.

Source: Signal Transduction Knowledge Environment - October 7, 2019 Category: Science Authors: Ma, J., Abram, C. L., Hu, Y., Lowell, C. A. Tags: STKE Research Articles Source Type: news