Protective effects of S100A8 on sepsis mortality: Links to sepsis risk in obesity and diabetes

Obesity and diabetes are independent risk factors for death during sepsis. S100A8, an alarmin, is related to inflammation, obesity, and diabetes. Here, we examine the role of S100A8 in sepsis of obesity and diabetes models. Injection of S100A8 prolongs the survival of septic mice induced by lethal endotoxemia, Escherichia coli injection, or cecal ligation and puncture. S100A8 decrease the LPS-induced expression of proinflammatory cytokines in peritoneal macrophages by inhibiting TLR4-mediated signals in an autocrine manner. db/db, ob/ob, and western diet-fed mice demonstrate reduced upregulation of S100A8 induced by LPS treatment in both serum and peritoneal cells. These mice also show shorter survival after LPS injection, and S100A8 supplementation prolonged the survival. While myelomonocytic cells-specific S100A8-deficient mice (Lyz2cre:S100A8floxed/floxed) exhibit shorter survival after LPS treatment, S100A8 supplementation prolonged the survival. Thus, myelomonocytic cell-derived S100A8 is crucial for protection from sepsis, and S100A8 supplementation improves sepsis, particularly in mice with obesity and diabetes. [Display omitted] •Obese and diabetic mice demonstrate impaired induction of S100A8 during endotoxemia•S100A8 suppresses TLR4-mediated inflammatory cytokine production•S100A8 from myelomonocytic cells is critical for survival during sepsis•S100A8 supplementation rescues mice with obesity and diabetes from septic death Physiology; Pathophysiology; Immunology.