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# Editorial: Hypoxia and inflammation: A two-way street

Philippe Saas, Guo-Chang Fan

► To cite this version:

Philippe Saas, Guo-Chang Fan. Editorial: Hypoxia and inflammation: A two-way street. Frontiers in Immunology, 2023, 14, pp.1171116. 10.3389/fimmu.2023.1171116. inserm-05005405

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OPEN ACCESS

EDITED AND REVIEWED BY

Pietro Ghezzi,
University of Urbino Carlo Bo, Italy

*CORRESPONDENCE

Philippe Saas

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Philippe.saas@efs.sante.fr

Guo-Chang Fan

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fangg@ucmail.uc.edu

SPECIALTY SECTION

This article was submitted to
Inflammation, a section of the journal
Frontiers in Immunology

RECEIVED 21 February 2023

ACCEPTED 01 March 2023

PUBLISHED 08 March 2023

CITATION

Saas P and Fan G-C (2023) Editorial: Hypoxia and inflammation: A two-way street.

Front. Immunol. 14:1171116.
doi: 10.3389/fimmu.2023.1171116

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Editorial: Hypoxia and
inflammation: A two-way street

Philippe Saas ID ¹,²* and Guo-Chang Fan ID ³*

¹EFS, Recherche et Développement, Grenoble, France, ²Université Grenoble-Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France, ³Department of Pharmacology & Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States

KEYWORDS

hypoxia, HIF, inflammation, macrophages, hematopoietic progenitor and stem cells, inflammatory diseases, efferocytosis

Editorial on the Research Topic

Hypoxia and inflammation: A two-way street

Oxygen homeostasis is crucial for survival, and mammals have developed fine regulatory mechanisms in response to oxygen variations. The role of oxygen availability in physiological and pathological processes catches more and more attention. Oxygen tension in mammalian body varies depending on the considered tissue. An oxygen gradient exists between the air we breathe (~21% O₂), present in lung alveoli, and the oxygen tension found in other mammalian tissues. Accordingly, normoxia is tissue-dependent. Within a given tissue, oxygen distribution varies. Indeed, the partial oxygen pressure (PO₂) of the bone marrow (BM) -the primary site of hematopoiesis- is different in the human sternum and iliac crest marrow. Reduced oxygen availability -a situation called physiological hypoxia- is detected in localized areas in the BM that are critical for hematopoietic stem and progenitor (HSPC) differentiation. For a same organ such as the spleen, PO₂ values differ from one species to another, reflecting the heterogeneous perfusion of this secondary lymphoid organ. Besides the physiological variations of oxygen availability, pathological hypoxia is a common hallmark of several inflammatory diseases such as cancers and infectious diseases. *In vitro* experiments performed in standard cell culture incubators (5% CO₂, 75% humidity) should be considered as hyperoxic conditions (~18.5% O₂) for cultured cells. Therefore, the terms hyperoxia, normoxia, and hypoxia should be used contextually rather than absolutely, since oxygenation is variable *in vivo*. For better interpretation, oxygenation should always be defined quantitatively (1).

The main cellular oxygen sensors are hypoxia-inducible factors (HIFs) with HIF-1α
being the most studied transcription factor. Activation of HIF-1α by hypoxia leads to its
translocation to the nucleus (for details on HIF-1α activation, refer to Thomas et al.). After
translocation, HIF-1α binds to hypoxia-response elements, which initiate the transcription
of hypoxia-sensitive genes. These genes code for different proteins (e.g., vascular
endothelial growth factor [VEGF], erythropoietin [EPO], or glucose transporter 1)
decreasing cellular oxygen consumption and/or increase oxygen delivery (1). Hypoxia
influences immune cell functions by regulating metabolic pathways, and can be a
pathogenic factor in some inflammatory diseases. Conversely, inflammation can lead to
local hypoxia. The aim of this Research Topic was to gather articles discussing/studying the
relationship between hypoxia and inflammation. This topic collects five original research manuscripts and one review dealing with six different diseases associated with hypoxia and inflammation. Four diseases affect the lungs: sarcoidosis (Jeny et al.), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (Florentin et al.) as chronic diseases and coronavirus disease 2019 (COVID-19) (Diaz-Garcia et al.) as an acute disease. Atherosclerosis (Thomas et al.) and myocardial infarction (MI) (Qi et al.) target the cardiovascular system. Several cell types are exposed to hypoxia, including a rat myoblast cell line (Qi et al.), human circulating leukocytes (Diaz-Garcia et al.), mouse and human HSPC (Florentin et al.) and macrophages (Thomas et al.; Emam et al.; Jeny et al.).

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% O₂, 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% O₂, 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% O₂ 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-1α target gene. Furthermore, inhibiting the VEGF/VEGFR1 axis could limit hypoxia-induced 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 pro-inflammatory and anti-inflammatory/resolving macrophages) (6).

HIF1α-dependent glycolysis favors the M1 phenotype, while M2 macrophages seem to be HIF-independent (7). Thomas et al. discuss the bidirectional interaction between hypoxia/HIF-1α and cholesterol metabolism in atherosclerosis. In atherosclerotic plaques, cholesterol engulfed by macrophages trigger reactive oxygen species (ROS) synthesis, responsible for HIF-1α activation. The liver X receptor pathway stimulated by cholesterol-derived oxysterols may interact directly with HIF-1α. Conversely, hypoxia and HIF-1α 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% O₂, 24 hours). Exposure of MDMs from patients with active sarcoidosis (AS) to hypoxia activates HIF-1α and pro-inflammatory cytokine synthesis without activating the NF-κB pathway. Hypoxia confers also to MDMs of AS patients, a pro-fibrotic profile with the increase of pro-fibrotic factors (e.g., VEGFA, 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-1α 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% O₂) to hypoxic conditions (1.5% O₂) 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 pro-inflammatory 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-1α (10). This last work is interesting for this editorial, since respiratory burst-induced hypoxia activates macrophage EPO signaling to promote inflammation resolution. This burst induces a local hypoxia that activates HIF-1α. HIF-1α 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.

## Funding

PS is supported by the Agence Nationale de la Recherche (ANR-11-LABX-0021 to Labex LipSTIC), the Conseil Régional de Franche-Comté ("Soutien au LabEX LipSTIC"). G-CF is supported by NIH grants R01 GM-132149, and HL-160811, and R35 GM-149538.

## Acknowledgments

We would like to thank all the authors for their contribution to this Research Topic and all peer reviewers for their insightful comments.

## References

1. Keeley TP, Mann GE. Defining physiological normoxia for improved translation of cell physiology to animal models and humans. *Physiol Rev* (2019) 99(1):161-234. doi: 10.1152/physrev.00041.2017

2. Cartwright IM, Colgan SP. The hypoxic tissue microenvironment as a driver of mucosal inflammatory resolution. *Front Immunol* (2023) 14:1124774. doi: 10.3389/fimmu.2023.1124774

3. Pietrobon AJ, Andrejew R, Custódio RWA, Oliveira LM, Scholl JN, Teixeira FME, et al. Dysfunctional purinergic signaling correlates with disease severity in COVID-19 patients. *Front Immunol* (2022) 13:1012027. doi: 10.3389/fimmu.2022.1012027

4. Dorneles GP, Teixeira PC, da Silva IM, Schipper LL, Santana Filho PC, Rodrigues Junior LC, et al. Alterations in CD39/CD73 axis of T cells associated with COVID-19 severity. *J Cell Physiol* (2022) 237(8):3394-407. doi: 10.1002/jcp.30805

5. Watanabe S, Alexander M, Misharin AV, Budinger GRS. The role of macrophages in the resolution of inflammation. *J Clin Invest* (2019) 129:2619-28. doi: 10.1172/JCI124615

6. Xue J, Schmidt SV, Sander J, Draffeln A, Krebs W, Quester I, et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. *Immunity* (2014) 40:274-88. doi: 10.1016/j.immuni.2014.01.006

## Conflict of interest

PS is the shareholder of Med'Inn'Pharma, related to the development of anti-inflammatory treatment. At this stage, the mechanisms of action of this treatment has no link with hypoxia.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

7. Taylor CT, Doherty G, Fallon PG, Cummins EP. Hypoxia-dependent regulation of inflammatory pathways in immune cells. *J Clin Invest* (2016) 126(10):3716-24. doi: 10.1172/JCI84433

8. Kambouchner M, Pirici D, Uhl JF, Mogoanta L, Valeyre D, Bernaudin JF. Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas. *Eur Respir J* (2011) 37(4):835-40. doi: 10.1183/09031936.00086410

9. Ushach I, Zlotnik A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. *J Leukoc Biol* (2016) 100(3):481-9. doi: 10.1189/jlb.3RU0316-144R

10. Luo B, Wang J, Liu Z, Shen Z, Shi R, Liu YQ, et al. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution. *Nat Commun* (2016) 7:12177. doi: 10.1038/ncomms12177

11. Wang YT, Trzeciak AJ, Rojas WS, Saavedra P, Chen YT, Chirayil R, et al. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments. *Cell Metab* (2023) 35(2):316-331.e6. doi: 10.1016/j.cmet.2022.12.005

12. Court M, Petre G, Atifi ME, Millet A. Proteomic signature reveals modulation of human macrophage polarization and functions under differing environmental oxygen conditions. *Mol Cell Proteomics* (2017) 16(12):2153-68. doi: 10.1074/mcp.RA117.000082