Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that remains a leading cause of death in intensive care units worldwide. The global burden of sepsis is difficult to ascertain, the latest statistics report that in 2017 there were 48.9 million cases and 11 million sepsis-related deaths worldwide, which accounted for almost 20% of all global deaths.
Two phases have been recognized in this disease: an early inflammatory phase and a late immunosuppressive stage; however, these two stages can overlap. Several characteristic alterations have been described during sepsis including decreased human leukocyte antigen (HLA)-DR expression, overexpression of immune checkpoints, and T cell exhaustion. Monocytes/macrophages are believed to play an important role in this context by functioning as orchestrating hubs of the host immune response. They participate in both phases of sepsis, firstly by releasing inflammatory cytokines that contribute to inflammatory pathologies, and secondly by adopting an immune depressive phenotype, characterized by a diminished response to pathogen signatures, inflammatory stimuli, and, therefore, secondary infections. During the transition from a pro-inflammatory to an immunosuppressive phenotype, monocytes/macrophages adopt protective functions including increased phagocytosis, bactericidal activity, and tissue remodeling. Furthermore, they participate in the induction of T cell exhaustion through the expression of immune checkpoints. This reflects their functional plasticity during human sepsis.
The phenotypic switch of monocytes/macrophages during the course of sepsis is critically controlled by hypoxia-inducible factor-1a (HIF1a) expression. HIF1a is a major regulator of oxygen homeostasis in mammals. Under normoxia, oxygen and prolyl hydroxylases hydroxylate HIF1a, inducing its ubiquitination and further proteasomal degradation after binding of ubiquitin ligase proteins such as Von Hippel-Lindau (VHL) protein. During the inflammatory phase of sepsis hypoxic conditions suppress hydroxylation of HIF1a resulting in its accumulation and nuclear translocation to activate critical metabolic adaptation pathways. In blood, an abnormally low level of oxygen is known as hypoxemia. How hypoxia and HIF1a driven metabolic adaptations affect the course of infections and sepsis outcome is incompletely understood. Whereas hypoxemia alone is considered a bad prognostic marker, an improved mechanistic understanding of hypoxia driven adaptations might reveal important cues linking immune status and outcome in sepsis patients.
This Research Topic aims to shed light on the role of Hypoxia-inducible factors in immunometabolic reprogramming during sepsis. We welcome the submission of Original Research articles, Reviews, and Mini-Reviews, which cover, but are not limited to, the following topics:
1. Immune-functional reprogramming during sepsis, the role of hypoxia-inducible factors.
2. Hypoxia, hypoxia-inducible factors, and involved immunological pathways as predictors in sepsis clinical evolution.
3. Molecular and cellular immune mechanisms underlying clinical evolution of septic patients.
4. Role of hypoxia in myeloid cell development and potential implication in sepsis.
