Hypoxia-inducible factor-1 drives divergent immunomodulatory functions in the pathogenesis of autoimmune diseases

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric (HIF-1α/ HIF-1β) transcription factor in which the oxygen-sensitive HIF-1α subunit regulates gene transcription to mediate adaptive tissue responses to hypoxia. HIF-1 is a key mediator in both regulatory and pathogenic immune responses, because ongoing inflammation in localized tissues causes increased oxygen consumption and consequent hypoxia within the inflammatory lesions. In autoimmune diseases, HIF-1 plays complex and divergent roles within localized inflammatory lesions by orchestrating a critical immune interplay sponsoring the pathogenesis of the disease. In this review, we have summarized the role of HIF-1 in lymphoid and myeloid immunomodulation in autoimmune diseases. HIF-1 drives inflammation by controlling the Th17/T_reg /Tr1 balance through the tipping of the differentiation of CD4⁺ T cells in favour of pro-inflammatory Th17 cells while suppressing the development of anti-inflammatory T_reg /Tr1 cells. On the other hand, HIF-1 plays a protective role by facilitating the expression of anti-inflammatory cytokine IL-10 in and expansion of CD1d^hi CD5⁺ B cells, known as regulatory B cells or B10 cells. Apart from lymphoid cells, HIF-1 also controls the activation of macrophages, neutrophils and dendritic cells, thus eventually further influences the activation and development of effector/regulatory T cells by facilitating the creation of a pro/anti-inflammatory microenvironment within the autoinflammatory lesions. Based on the critical immunomodulatory roles that HIF-1 plays, this master transcription factor seems to be a potent druggable target for the treatment of autoimmune diseases.