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

Abstract

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.

One-sentence summary:

Without the kinase Lyn, the adaptor protein CARD9 amplifies cytokine production in autoimmune disease.

Editor’s summary:

Lyn-deficient autoimmunity shows its CARDs

Both the adaptor protein CARD9 and loss of the kinase Lyn are associated with autoimmune disease, notably colitis and inflammatory bowel disease. Ma et al. explored this connection in mice and found that CARD9 amplified Toll-like receptor signaling and subsequent cytokine production in Lyn-deficient bone marrow–derived dendritic cells, but not macrophages. Deleting Card9 or genes encoding Src-family kinases in dendritic cells prevented the development of Lyn deficiency–associated colitis in mice. These findings suggest that targeting CARD9 or its associated kinases may therapeutically relieve inflammation in patients with autoimmune disease and that exploring the biological consequences of CARD9 polymorphisms is warranted.