Abstract 10144: Xcr1 ⁺ Dendritic Cell-Induced Cd4 ⁺ T Helper-1 Activation Leads to Exacerbation of Remodeling After Myocardial Infarction

Background and Aim: Immune response including T cell activation after myocardial infarction (MI) is important mechanism in cardiac remodeling. We established a new model of ischemic cardiomyopathy using SR-BI KO/ApoeR61 h/h (SRBI KO) mice in which MI is induced by high fat diet (HFD) for 7 days. We aimed to clarify the precise mechanism leading to post-MI cardiac remodeling: activation of inflammatory CD4 + T-cell subsets and conventional dendritic cells (cDCs), using our non-surgical MI, coronary ligation MI and conditional cCDs KO mice model. Methods and Results: Probucol, a potent antioxidant, was known to improve cardiac remodeling in rat MI model. Using SRBI +/- mice as a non-MI control group, we fed SRBI KO mice HFD to induce MI (non-treatment group) and added probucol (treatment group). With probucol treatment, survival rate and EF were improved, and fibrosis area was reduced. We analyze CD4 + cell subsets in the heart, blood and spleen. Th1 was predominantly increased and activated in border and infarcted area, and decreased with probucol treatment. RNA-seq revealed, specifically Th1 related chemokines, CXCR3 was down-regulated with probucol treatment. Flow data revealed, CXCR3 was highly expressed in Th1 (up to 50%) and decreased with probucol treatment. To elucidate the mechanism of the predominant activation of Th1 after MI, we analyze the dynamics of cDCs. XCR1 + cDCs was activated and decreased with probucol treatment. Furthermore, CXCR3 ligands, CXCL9 and CXCL10, were highly expressed in XCR1 + cDCs (up to 50%). In bone marrow, siglec-H – Ly6C – pre-DCs (XCR1 + cDCs lineage) were increased in non-treatment group and also in coronary ligation MI model, and decreased with probucol treatment. Finally, to confirm the induction of post-MI Th1 type inflammation by XCR1 cDCs, we conducted the conditional depletion of XCR1 + cDCs. In XCR1 KO mice, infiltration of CXCR3 + Th1 in the infarcted area and fibrosis area was decreased, and deterioration of EF, which was evaluated by cardiac MRI, was suppressed after MI. Conclusions: The predominant activation of Th1 after MI exacerbated cardiac remodeling. CXCR3 chemokine system were characteristic of Th1 and XCR1 + cDCs. The modulation of Th1- XCR1 + cDCs interaction could be a novel therapeutic target in post-MI remodeling.