Crosstalk between Hypoxia and ER Stress Response: a Key Regulator of Macrophage Polarization
Open accessAbstract
Macrophage activation and polarization are closely linked with metabolic rewiring, which is required to sustain their biological functions. These metabolic alterations allow the macrophages to adapt to the microenvironment changes associated with inflammation or tissue damage (hypoxia, nutrient imbalance, oxidative stress, etc.) and to fulfill their highly energy-demanding proinflammatory and anti-microbial functions. This response is integrated via metabolic sensors that coordinate these metabolic fluxes with their functional requirements. Here we review how the metabolic and phenotypic plasticity of macrophages are intrinsically connected with the hypoxia stress sensors and the unfolded protein response in the endoplasmic reticulum, and how these molecular pathways participate in the maladaptive polarization of macrophages in human pathology and chronic inflammation.
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IRE1α-XBP1 activity shapes cytokine production, metabolic rewiring, and immune function in these cells.
“ER stress pathways intersect with HIF signaling in these cells, with IRE1α XBP1 activity shaping cytokine production, metabolic rewiring, and immune function [266,267].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [266]
Macrophages are sensitive to hypoxia and under hypoxia obtain an M2/immunosuppressive phenotype instead of the M1/antitumoral polarization in normoxia.
“It is important that macrophages are sensitive to hypoxia and instead of the M1/antitumoral polarization in normoxia, under such circumstances they obtain M2/immunosuppressive phenotype [49].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [49]
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References 168 · Cited by 175
- Authors
- Díaz-Bulnes, P., Saiz, M. L., López-Larrea, C., & Rodríguez, R. M.
- Affiliations
- Hospital Universitario Central de Asturias (ES)
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2020-01-08
- Volume
- 10
- Pages
- 2951-2951
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC6961549
- OpenAlex
- W3000622012
- Cited by
- 175
- References
- 168
- Citations by year
- 2026: 36 · 2025: 26 · 2024: 32 · 2023: 24 · 2022: 29 · 2021: 23 · 2020: 5
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Repositorio Institucional de Asturias (Gobierno del Principado de Asturias) (submittedVersion, cc-by-nc)
- Funders
- Gobierno del Principado de Asturias (IDI/2018/144)
- European Commission (PI17/01244, 2018-2022, RD16/0009, 2013-2016, RD16/0009/0020)
- Instituto de Salud Carlos III (PI16/, RD16/0009, 2013-2016, PI16/01318, RD16/0009/0020, PI17/01244, PI19/00184)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- macrophage polarization, hypoxia, endoplasmic reticulum stress, unfolded protein response, metabolic reprogramming, metabolic plasticity, chronic inflammation, metabolic sensors, macrophage activation, oxidative stress
- MeSH terms
- Animals, Hypoxia, Humans, Inflammation, Macrophage Activation, Macrophages, Signal Transduction, Endoplasmic Reticulum Stress
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