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 response. Based on findings from cancer research, the role of the hypoxic tumor microenvironment in suppressing the type 1 interferon response and subsequent immune activation has steered autoimmunity research toward the immunomodulatory effects of hypoxia-induced activation of the hypoxia-inducible factor-1α (HIF-1α) pathway. Although the immunostimulatory effects of HIF-1α in certain autoimmune diseases are well documented, its role and underlying mechanisms remain controversial. Here, we present an overview of HIF-1α-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-1α exerts in various autoimmune disorders. Finally, we will examine the pharmacological potential of HIF-1α modulation to regulate innate immunity prior to the development of autoimmune diseases.