Reorganization of resident macrophages and recruited monocytes in the heart during sepsis

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Sepsis is defined as life-threatening organ dysfunction, caused by a dysregulated host response to infection. Survivors of sepsis have long-lasting consequences and notably an increased risk of developing cardiovascular disease. Changes in intra-organ immune homeostasis may be responsible for the observed chronic failures and lower resilience to new infections. To characterize reorganization in number and phenotype of resident macrophages and recruited monocytes in the heart during sepsis using a mouse model of sepsis. Using a sublethal cecal ligation and puncture (CLP) model of sepsis, macrophages subtypes were analyzed by flow cytometry for 21 days, and cardiac function was assessed by echocardiography and histology. Cx3cr1CreER/+R26tdTomato/+ mice were used for fate-mapping studies. In a model of sublethal sepsis induced by CLP (25% mortality, 15% weight loss), a fleeting and rapidly reversible alteration of cardiac function (24 h to 48 h) characterized by a decrease in the shortening fraction was observed. This alteration was not associated with cardiac fibrosis after histological analysis using Sirius red (0% at day 28). Surviving mice recovered their weight and normal activity on day 14. Leukocyte count showed a significant increase in intracardiac macrophages (CD45+, CD11b+, CD64+), with a maximum increase on day 14. Phenotypic analysis revealed a decrease in the pool of Timd4+ macrophages (resident macrophages), and a significant increase in the pool of CCR2+ macrophages (recruited macrophages). This increase persisted for 14 days. The MHC2+ macrophages (resident macrophages) population was globally stable over time. Fate mapping analysis showed a high turnover of the intracardiac macrophages pool (CD45+, CD11b+, CX3CR1+) with 40% turnover in 21 days in control mice. After CLP, we observed a significant decrease in the pool of resident macrophages, which is consistent with the disappearance reaction hypothesis. In this study, we described the evolution of tissue macrophages and variations in all three subsets of macrophages in the heart after sepsis. Using our fate mapping approach, we confirmed that the increased number of tissue macrophages after sepsis was mainly due to the recruitment of monocytes.