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

Daisuke Miyashita; Ryota Inoue; Takahiro Tsuno; Tomoko Okuyama; Mayu Kyohara; Chigusa Nakahashi-Oda; Kuniyuki Nishiyama; Setsuko Fukushima; Yutaro Inada; Yu Togashi; Akira Shibuya; Yasuo Terauchi; Jun Shirakawa

doi:10.1016/j.isci.2022.105662

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

iScience. 2022 Nov 23;25(12):105662. doi: 10.1016/j.isci.2022.105662. eCollection 2022 Dec 22.

Authors

Daisuke Miyashita^{1

2}, Ryota Inoue^{1

2}, Takahiro Tsuno^{1

2}, Tomoko Okuyama², Mayu Kyohara², Chigusa Nakahashi-Oda³, Kuniyuki Nishiyama^{1

2}, Setsuko Fukushima¹, Yutaro Inada², Yu Togashi², Akira Shibuya^{3

4}, Yasuo Terauchi², Jun Shirakawa^{1

2}

Affiliations

¹ Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Maebashi, Japan.
² Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama-City University, Yokohama, Japan.
³ Department of Immunology, Faculty of Medicine, and R&D Center for Innovative Drug Discovery, University of Tsukuba, Tsukuba, Japan.
⁴ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.

Abstract

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 (Lyz2 ^cre :S100A8 ^{floxed/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.

Keywords: immunology; pathophysiology; physiology.