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)-1alpha 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 HIF1alpha is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1alpha (IRE1alpha/XBP1) axis in order to initiate HIF1alpha-dependent production of cytokines such as IL1beta, IL6 and VEGF-A. Knockout of either HIF1alpha or IRE1alpha 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 HIF1alpha, may co-regulate immune adaptation to low oxygen. Keywords: HIF1alpha, Retina, Angiogenesis, Inflammation, IRE1alpha, Myeloid, Mononuclear phagocytes, Microglia, Hypoxia, ER stress