Editorial: Hypoxia and inflammation: A two-way street

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The in vitro oxygen-glucose deprivation (OGD) model is utilized for the culture of H9c2, a myoblast cell line derived from embryonic rat heart, in a sugar-free medium under hypoxic conditions (1% O 2 , 12 hours). Qi et al. show that OGD induces NLRP3 inflammasome activation; whereas treatment of H9c2 cells with ginsenoside-Rh2 (a Chinese medicine compound) and exosomes collected from mesenchymal stem cells reduces this activation. This may represent a new therapeutic approach for the reduction of ischemia-induced cardiac inflammation.
Diaz-Garcia et al. report that circulating soluble CD39 increases in patients developing a severe form of COVID-19. This increase is associated with increased CD39 expression on circulating T and NK cells, but also with hypoxemia severity and clinical prognosis. In vitro experiments using peripheral blood-derived mononuclear cells (PMBCs) cultured under hypoxic conditions (9% O 2 , 16 hours) confirm this enhanced expression of CD39 on T and NK cells, while decreased expression of CD73 is observed. CD73 is responsible for the final degradation of adenosine triphosphate and diphosphate into the immunosuppressive adenosine (2). Accumulation of these two adenosine nucleotides resulting from altered CD73 expression stimulates purinergic receptors expressed by platelets and monocytes. This leads to platelet and monocyte activation inducing both thrombus formation and inflammatory cytokine production. These results are recently confirmed by others (3,4). In severe COVID-19, hypoxia could be responsible for uncontrolled thrombo-inflammation.
In two mouse models -mice exposed to 10% O 2 for three weeks and the cigarette smoke-induced COPD model-, Florentin et al. determine the effects of chronic hypoxia on HSPC proliferation. Hypoxia induces HSPC proliferation via the upregulation of VEGF and its receptor, VEGF receptor 1 (VEGFR1). HIF1A silencing in both human and mouse HSPC reduces hypoxia-induced proliferation and hypoxia-induced VEGFR1 mRNA expression. VEGFR1 is thus another HIF-1a target gene. Furthermore, inhibiting the VEGF/VEGFR1 axis could limit hypoxiainduced inflammation.
Macrophages, a heterogeneous cell population with a high plasticity, may arise from HSPCs during embryogenesis to become tissue-resident macrophages. Alternatively, during inflammation, macrophages are differentiated from monocytes (MDMs) (5). Macrophages exert a vast range of functions characterized by an array of phenotypes with two extreme polarized phenotypes, M1 and M2 (schematically proinflammatory and anti-inflammatory/resolving macrophages) (6).
HIF1a-dependent glycolysis favors the M1 phenotype, while M2 macrophages seems to be HIF-independent (7). Thomas et al. discuss the bidirectional interaction between hypoxia/HIF-1a and cholesterol metabolism in atherosclerosis. In atherosclerotic plaques, cholesterol engulfed by macrophages trigger reactive oxygen species (ROS) synthesis, responsible for HIF-1a activation. The liver X receptor pathway stimulated by cholesterol-derived oxysterols may interact directly with HIF-1a. Conversely, hypoxia and HIF-1a favor the accumulation of cholesterol in macrophage by increasing its uptake and limiting its efflux. Hypoxia induces the accumulation of free cholesterol -a pro-inflammatory trigger-in advanced atherosclerotic plaques.
Jeny et al. investigate the role of hypoxia in M-CSF-induced human MDMs. Monocytes obtained from patients with pulmonary sarcoidosis and healthy controls are differentiated, and exposed to hypoxia (1.5% O 2 , 24 hours). Exposure of MDMs from patients with active sarcoidosis (AS) to hypoxia activates HIF-1a and proinflammatory cytokine synthesis without activating the NF-kB pathway. Hypoxia confers also to MDMs of AS patients, a profibrotic profile with the increase of pro-fibrotic factors (e.g., VEGF-A, and plasminogen activator inhibitor-1 [PAI-1]). This mixed pro-inflammatory/pro-fibrotic profile induced by hypoxia contrasts with the mild pro-fibrotic profile observed in MDMs from healthy donors. Expression of HIF-1a and PAI-1 in the nucleus of macrophage-derived epithelioid cells in pulmonary biopsies of AS patients supports the clinical relevance of these findings. Comparing atmospheric (~21% O 2 ) to hypoxic conditions (1.5% O 2 ) is appropriate here; physiologically, lung macrophages are exposed to atmospheric conditions. Contrarily, sarcoidosis granulomas are hypoxic (8). In contrast to M-CSF that generates less differentiated MDMs, GM-CSF promotes a proinflammatory phenotype in MDMs (9). Emam et al. determined the impact of host genetics (appreciated by single nucleic polymorphisms [SNP]) on the ability of GM-CSF-induced bovine MDMs to produce nitric oxide (NO) in response to Escherichia coli. Among the 43,066 SNPs studied, 60 SNPs of the bovine genome were statistically associated with NO production. Four genes belong to the Gene Ontology term "response to hypoxia". The authors speculate that modulation of these genes is indirectly related to hypoxia, but linked to respiratory/oxidative burst (i.e., the fast release of the ROS). Indeed, this burst generates hypoxia at the macrophage level and activates HIF-1a (10). This last work is interesting for this editorial, since respiratory burstinduced hypoxia activates macrophage EPO signaling to promote inflammation resolution. This burst induces a local hypoxia that activates HIF-1a. HIF-1a activation leads to EPO secretion that stimulates EPO receptor in an autocrine manner. EPO pathway increases apoptotic neutrophil elimination (the efferocytosis process) promoting the resolution phase of inflammation (10). Efferocytosis is critical, since neutrophils play a major role in depleting local oxygen in inflamed tissue (2). Chronic hypoxia increases efferocytic capacities of both murine and human macrophages (11,12). Thus, hypoxia could also promote inflammation resolution (2).
In conclusion, this Research Topic provides additional information on the relationship between hypoxia and inflammation.

Author contributions
All authors listed have made a substantial, direct and intellectual contribution to the work and approved it for publication.