Card9 deficiency accelerates experimental atherosclerosis.

Introduction There are accumulating evidences that innate and adaptive immunity play a major role in the development of atherosclerosis. Pattern-recognition receptors (PRRs) engagement including toll-like receptors and Dectins are involved in the modulation of immune response and atherosclerosis development but little is known about downstream signaling pathways. Card9 for Caspase recruitment domain-containing protein-9, is an adaptor protein expressed by antigen presenting cells required for PRRs-induced activation of myeloid cells. Objective We hypothesized that Card9 pathway regulates systemic immune response and impacts on the development of atherosclerosis. Method and results To evaluate the effect of Card9 deficiency on experimental atherosclerosis, we generated chimeric Ldlr -/- Card9 -/− and Ldlr -/- Card9 +/+ mice. After 8 weeks of high fat diet, cholesterolemia was not different between groups. We observed an increase of atherosclerosis plaque size in the aortic sinus in Ldlr -/- Card9 -/− mice compared to Ldlr -/- Card9 +/+ mice (+32%, P = 0.04). Using immunohistochemistry staining, we analyzed plaque composition and found a more inflammatory plaque phenotype in Ldlr -/- Card9 -/− mice when compared to control mice with an increase in both macrophage accumulation (+86%, P = 0.0005) and necrotic core size (+102%, P = 0.006). Card9 deficiency induced a deviation of the systemic immune response toward a pro-inflammatory profile. Lps/Ifn-γ-stimulated Card9 -/− bone marrow-derived macrophages (BMDM) produced less IL-10 (−22%, P < 0.05) than Card9 +/+ BMDM. Lps/Ifn-γ-stimulated splenocytes isolated from LDLr -/- Card9 -/− mice produced more IL-12p70 (+151%, P < 0.01) than splenocytes from LDLr -/- Card9 +/+ mice. Anti-CD3 stimulated CD4 + T cells from Ldlr -/- Card9 -/− mice produced less Ifn-γ (−92%, P < 0.05) and less IL-17A (−100%, P < 0.05) than control CD4 + T cells. Conclusion Card9 deficiency accelerated atherosclerosis development in mice and induced a more inflammatory plaque phenotype. [ABSTRACT FROM AUTHOR]