Rel+ macrophages disturbing cardiac niche contributes to cardiac dysfunction following sepsis.

BACKGROUND

Cardiac dysfunction is a major cause of high mortality in sepsis. A well-organized cardiac microenvironment, consisting of cardiomyocytes and non-cardiomyocytes, is essential for maintaining heart function. The mechanism is still unclear.

METHODS

Single-cell and single-nuclei RNA sequencing of the left ventricular tissues from cecal ligation and puncture-induced septic shock mice models were used to detect the change of cardiac cells. Immunofluorescence of myocardial tissue was conducted to validate key cell subpopulations, and PKM2 siRNA-loaded targeting nanomaterials were used to observe the role of Mac2.

RESULTS

The noncontractile phenotype of cardiomyocytes was major type following sepsis. Rel+ resident macrophages (Rel+ Mac), sepsis-specific cardiac resident macrophages subpopulation, presented metabolic reprogramming with high glycolysis signatures, established a pro-inflammatory niche in septic heart. Mechanistically, Rel+ Mac contributed to cardiomyocyte contractile phenotype switching after sepsis by ITGB1, ITGA9, LAMA2, ITGA4, IL6, TNF, VCAM1 and MMP13 signal axis. Furthermore, Rel+ Mac orchestrated broader microenvironment disruption by interacting with vascular leakage-associated venous endothelial cells and pericytes, vascular hypo-responsiveness associated smooth muscle cells, and cardiac matrix remodeling fibroblasts subpopulation FB3. Targeting Rel+ Mac metabolic reprogramming by PKM2 siRNA-loaded with nanomaterials protected cardiac function after sepsis.

CONCLUSIONS

Rel+ Mac, along with associated microcirculation and stromal cells, disrupt the cardiac niche and synergistically contribute to the occurrence of sepsis-induced cardiac dysfunction. Among which, Rel⁺ macrophages act as key contributors within a broader network (mitochondrial dysfunction, Ca²⁺ mishandling, oxidative stress). These results may provide targets and strategies for the treatment of sepsis-induced myocardial injury in a multifaceted and integrated manner.