Abstract 13005: Depletion of XCR1+ Conventional Dendritic Cell After Myocardial Infarction Improved Adverse Cardiac Remodeling via CXCR3 Chemokine Signaling

Abstract

Introduction: We have demonstrated immune reactions of probucol treatment on cardiac remodeling using SR-BI KO/ApoeR61 h/h (SRBI KO) mice in which ischemic myocardial injury is induced by high fat diet. In the previous study, we identified the role of XCR1 + conventional dendritic cells 1 (cDC1)-activated CD4 + T Helper-1 (Th1) cells after ischemic myocardial injury. Hypothesis: Deletion of XCR1 + cDC1 cells after myocardial infarction (MI) might improve adverse cardiac remodeling through the suppression of Th1 cells. Methods: Using Xcr1 +/DTRvenus mice, which allow the XCR1-expressing cell elimination by treatment with diphtheria toxin (DT), permanent coronary ligation was conducted. DT was injected into Xcr1 +/DTRvenus mice 1 day after MI (XCR1 depleted-MI group). We analyze cDCs and CD4 + T cell subsets by flow cytometry. Results: The XCR1 depleted-MI group showed improvement of EF evaluated by cardiac MRI (p<0.05). In CD4 + T cell subsets, Th1 and Tregs were significantly localized in border and infarcted area, while Th1 cells were decreased in XCR1 depleted-MI group (p<0.001). To elucidate the mechanism of the predominant reduction of Th1 cells, we focused on CXCR3 chemokine receptor and its ligands, CXCL9 and CXCL10. CXCR3 is enriched on Th1 in the heart after MI, while it is not enriched on Tregs. Regarding the precise source of CXCL9 and CXCL10 in the ischemic heart, the percentage of XCR1 + cDC1 cells were most predominant in the cDCs subsets expressing CXCL9 and CXCL10 (p<0.001). These results suggested that XCR1 + cDC1 cell-derived CXCL9 and CXCL10 are significant contributor to the chemotaxis of CXCR3 + Th1 cells after MI. Finally, we analyzed autopsy samples of human MI cases to demonstrate clinical significance. CXCR3 + Th1 and XCR1 + cDC1 cells were detected significantly more in the infarcted area than in marginal zone. Conclusions: The modulation of XCR1+cDC1-activated CXCR3 + Th1 cells could be a novel therapeutic target to reduce post-MI remodeling.