Ischemic myocardial injury results in sterile cardiac inflammation that leads to tissue repair, two processes controlled by mononuclear phagocytes. Despite global burden of cardiovascular diseases, we do not understand the functional contribution to pathogenesis of specific cardiac mononuclear phagocyte lineages, in particular dendritic cells. To address this limitation, we used detailed lineage tracing and genetic studies to identify bona fide murine and human CD103+ conventional dendritic cell (cDC)1s, CD11b+ cDC2s, and plasmacytoid DCs (pDCs) in the heart of normal mice and immunocompromised NSG mice reconstituted with human CD34+ cells, respectively. After myocardial infarction (MI), the specific depletion of cDCs, but not pDCs, improved cardiac function and prevented adverse cardiac remodeling. Our results showed that fractional shortening measured after MI was not influenced by the absence of pDCs. Interestingly, however, depletion of cDCs significantly improved reduction in fractional shortening. Moreover, fibrosis and cell areas were reduced in infarcted zones. This correlated with reduced numbers of cardiac macrophages, neutrophils, and T cells, indicating a blunted inflammatory response. Accordingly, mRNA levels of proinflammatory cytokines IL-1β and IFN-γ were reduced. Collectively, our results demonstrate the unequivocal pathological role of cDCs following MI.
Bibliographical noteFunding Information:
This work was supported by grants from the Canadian Foundation for Innovation (John R. Evans Leaders Fund to C.C.) and the Canadian Institutes of Health Research (CIHR) (MOP 125933 to C.C. and J.T., MOP 136802 to J.T., and MOP 133050 to C.C.), by Canadian HIV Cure Enterprise Team Grant HIG-133050 (to C.C. and E.H.), and by a National Research Foundation of Korea grant funded by the Korean government (2012R1A3A2026454 to G.T.O.). J.S.L. was supported by the Fonds de Recherche du Québec – Nature et Technologies. J.T. holds the Saputo Research Chair. C.C. was a recipient of a CIHR New Investigator Award and held a Société
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