CD169+ Macrophages Regulate Immune Homeostasis During Sepsis Through IL-10 Production and LPS Clearance

Sepsis accounts for 6 million deaths worldwide each year, and currently, sepsis management is limited to supportive care and antibiotics. Our current knowledge of the cellular mechanisms and precisely, immune cell populations that regulate the inflammatory pathways during sepsis is limited. We report that CD169+ macrophages and signaling pathways are critical for protection against sepsis shock by using CD169-diphtheria toxin receptor (DTR) mice to deplete CD169+ macrophage. We show that in the absence of these macrophages, mice treated with sublethal LPS or cecal slurry fail to survive and exhibit increased production of inflammatory cytokines. Mechanistically, CD169+ macrophages control lethal inflammatory responses via IL-10 as CD169+ macrophage-specific deletion of IL-10 increased the susceptibility to LPS and the recombinant IL-10 reduced LPS-induced lethality in mice lacking CD169+ macrophages. Furthermore, CD169+ macrophages play a role in LPS clearance and CD169+ macrophage-deficient mice exhibit increased splenic dissemination of LPS. These findings reveal a pivotal homeostatic role for CD169+ macrophages during sepsis.