Conventional Dendritic Cells Impair Recovery after Myocardial Infarction

Abstract

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.

Leukocyte-Dependent Regulation of Cardiac Fibrosis

“…With CD11c + cell depletion, 24 weeks after TAC, mice exhibit reduced LV fibrosis and decreased expression of fibroblast activating genes (Wang et al, 2017). These studies are met with similar critiques regarding lack of DC specificity, however, studies using a more specific model of cDC ablation also show decreased LV fibrosis 3 weeks post-MI (Lee et al, 2018). These findings are further supported by earlier studies which show cardiac and splenic DC activation and expansion 8 weeks post-MI (Ismahil et al, 2014).…”

Dendritic Cells and T Cells, Partners in Atherogenesis and the Translating Road Ahead

“…In line with these findings, the CD103 + DCs subset in the aortic wall expanded in response to Flt-3L injection, and was absent in mice deficient in Flt-3, indicating that the development of the CD103 + DCs requires Flt-3/Flt-3L interaction, and they are derived from classical Flt3L-dependent pre-DC precursors (18). Recently, a lineage tracing study revealed that the CD103 + DCs in the cardiovascular tissues could be developed from an intermediate CD103 − CD11b − DC subset that expressed IRF8 and expanded readily in response to Flt-3L administration (34).…”

Lack of the E3 Ubiquitin Ligase March1 Affects CD8 T Cell Fate and Exacerbates Insulin Resistance in Obese Mice

“…Epididymal AT was harvested and minced into small pieces. Single cells were isolated by enzymatic digestion for 20 min at 37 • C with gentle shaking using a collagenase mixture containing collagenase I, collagenase XI, and hyaluronidase (Sigma) in Hanks balanced salt solution containing Ca + /Mg + and 5% FBS (Wisent), as described (27). After digestion, the single cells and remaining tissue were passed through a 70-µm cell strainer.…”