The Role of HIF-1α in Innate Immune Mechanisms and Autoimmunity: A Double-Edged Sword

Millions of people all around the world are affected by autoimmune diseases, characterized by immune-mediated destruction of cells or tissues and consequent organ dysfunction.Recently, the role of innate immunity in autoimmune disease pathogenesis has been established, with an emphasis on the type 1 interferon (T1-IFN) response.Based on findings from cancer research, the role of the hypoxic tumor microenvironment in suppressing the T1-IFN response and subsequent immune activation have steered autoimmunity research towards the immunomodulatory effects of hypoxia-induced activation of the hypoxia-inducible factor-1 (HIF-1) pathway.Although the immunostimulatory effects of HIF-1 in certain autoimmune diseases are well documented, its role and underlying mechanisms remain controversial.Here, we present an overview of HIF-1-mediated immunomodulation and gain insight into the mechanisms behind the contradictory effects.We will discuss mechanisms through which disruptions in innate immunity contribute to autoimmune disease pathogenesis and the divergent immunomodulatory effects that HIF-1 exerts in various autoimmune disorders.Finally, we will examine the pharmacological potential of HIF-1 modulation to regulate innate immunity prior to the development of autoimmune disease. Highlights Innate immunity is a key player in the pathogenesis of autoimmune diseases Hypoxia-induced HIF-1 activation suppresses the innate T1-IFN response in cancer HIF-1 employs several context-dependent mechanisms to influence parenchymal cells to either suppress or stimulate innate immune mechanisms HIF-1 modulation prior to autoimmune disease onset holds pharmacological potential to modulate innate immune responses