Type 1 conventional dendritic cell mitochondrial metabolism promotes adverse tissue remodeling after organ injury 2258277

Abstract

Abstract Introduction Type 1 conventional dendritic cells [cDC1] are known for their role in antiviral and cancer immune responses, yet their function in the response to tissue injury, and underlying molecular mechanisms, remains unclear. A prominent feature of tissue repair is the clearance of dying cells by efferocytosis, which fuels mitochondrial metabolism in the phagocyte. Herein, we reveal the contribution of cDC1s to adverse tissue remodeling following organ injury. Further, we discover that mitochondrial metabolism in cDC1s contributes to the maladaptive response. Methods We studied a clinically-relevant model of tissue injury and performed left anterior descending artery ligation to induce myocardial infarction [MI] using Irf8 + 32-/- [cDC1-/-] and Xcr1cre QPCfl/fl mouse lines, which disables mitochondrial metabolism in cDC1s. Echocardiography was used to track heart function over time. Acute injury was assessed using vital dyes to measure ratio of ischemic injury to the area at risk during the acute stage of injury. We evaluated cell phenotype, location, and activation by flow cytometry of the heart, spleen, and mediastinal lymph nodes [mLN] and with single cell RNA sequencing. Results cDC1 populations increased in the mLN and heart 7 days post-injury. scRNA sequencing of DC-enriched mLN on day 7 revealed an increased ratio of both resident and migratory, activated DCs and a reduction of pDCs. Concurrently, there was a reduction in the number of CD8 T cells in the injured hearts of cDC1-/- mice, by flow cytometry. cDC1 loss was associated with improved cardiovascular function on day 28 with no change in injury or function on day 7. This improvement was recapitulated in Xcr1cre/+ QPCfl/fl mice. These data indicate that cDC1 mitochondrial metabolism mediates maladaptive chronic inflammation and long-term damage in the injured heart. Conclusion Our findings more broadly implicate cDC1 mitochondrial metabolism in a maladaptive role in the resolution of chronic inflammation following tissue injury. Funding Source T32 AI007476 Topic Categories Classical and Non-Classical Antigen Presenting Cells (APC)