Macrophage Hypoxia Signaling Pathways and Their Roles in Sepsis

Mu Yuan,1,2 Lixing Tian,1,2,* Xiang Xu1– 3,* 1Department of Stem Cell and Regenerative Medicine, National Key Laboratory of Trauma and Chemical Poisoning, Army Characteristic Medical Center, Army Medical University, Yuzhong District, Chongqing, 400042, People’s Republic of China; 2Central Laboratory, State Key Laboratory of Trauma, Burn, and Combined Injury, Army Characteristic Medical Center, Army Medical University, Yuzhong District, Chongqing, 400042, People’s Republic of China; 3Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Science and Technology Achievement Incubation Center, Kunming Medical University, Chengguan District, Kunming, 650500, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiang Xu, Email [email protected] Lixing Tian, Email [email protected]: Sepsis is a severe systemic inflammatory response syndrome, and macrophages play a crucial role in its pathogenesis. In recent years, more and more attention has been paid to the molecular signaling pathways of hypoxia, especially hypoxia-inducible factor 1-alpha (HIF-1α) and its related metabolic reprogramming, which have shown their importance in regulating the inflammatory response and functional state of macrophages. At present, although a large number of studies have explored the functional changes of macrophages in sepsis, there are still many unsolved mysteries about the specific mechanism and clinical significance of the effect of hypoxia signaling pathway on macrophage function and disease progression. In this review, the metabolic pathways regulated by HIF-1α, the activation of inflammasomes, the reprogramming of cell functions, and the effects of hypoxia-related signaling pathways on macrophage function and the pathological process of sepsis were summarized. Combined with the latest single-cell transcriptomics data and molecular mechanism research, we systematically explore the potential therapeutic targets and intervention strategies, which provide theoretical basis and research direction for the precise treatment of sepsis.Keywords: sepsis, macrophages, hypoxia, HIF-1α, metabolic reprogramming, inflammasome, therapeutic target