HIF1α-dependent hypoxia response in myeloid cells requires IRE1α

Journal of Neuroinflammation

Research

Randal J. Kaufman¹  Roberto Diaz-Marin²  Rachel Juneau²  Mikhail Sergeev²  Ariel M. Wilson²  François Binet²  Christina Sawchyn²  Gaëlle Mawambo²  Agnieszka Dejda²  Frédérick A. Mallette²  Przemyslaw Sapieha³  Guillaume Blot³  Malika Oubaha⁴  Sergio Crespo-Garcia⁵  El Bachir Affar⁶  Yusuke Ichiyama⁷ 

[1]Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Rd, 92037, La Jolla, CA, USA

[2]Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, 5415 De L’Assomption Boulevard, H1T 2M4, Montréal, QC, Canada

[3]Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, 5415 De L’Assomption Boulevard, H1T 2M4, Montréal, QC, Canada

[4]Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, H1T 2M4, Montréal, QC, Canada

[5]Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, 5415 De L’Assomption Boulevard, H1T 2M4, Montréal, QC, Canada

[6]Départment de Sciences Biologiques, Université du Québec À Montréal (UQAM), H2X 1L4, Montréal, QC, Canada

[7]Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, 5415 De L’Assomption Boulevard, H1T 2M4, Montréal, QC, Canada

[8]School of Optometry, University of Montreal, H3T1P1, Montreal, QC, Canada

[9]Department of Medicine, University of Montreal, Montreal, Canada

[10]Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, Université de Montréal, H1T 2M4, Montréal, QC, Canada

关键词: HIF1α;    Retina;    Angiogenesis;    Inflammation;    IRE1α;    Myeloid;    Mononuclear phagocytes;    Microglia;    Hypoxia;    ER stress;   

DOI  :  10.1186/s12974-023-02793-y

 received in 2022-06-07, accepted in 2023-04-24,  发布年份 2023

来源: Springer

【 摘 要 】

Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.

【 授权许可】

CC BY   
© The Author(s) 2023

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