HIF1[alpha]-dependent hypoxia response in myeloid cells requires IRE1[alpha]

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)-1[alpha] 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 HIF1[alpha] is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1[alpha] (IRE1[alpha]/XBP1) axis in order to initiate HIF1[alpha]-dependent production of cytokines such as IL1[beta], IL6 and VEGF-A. Knockout of either HIF1[alpha] or IRE1[alpha] 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 HIF1[alpha], may co-regulate immune adaptation to low oxygen.