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/Treg/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 Treg/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 CD1dhiCD5+ 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. Hypoxia‐inducible factor‐1 is a master transcription factor, which regulates different gene transcriptions in response to hypoxia following an oxygen‐sensitive mechanism. HIF‐1 modulates lymphoid and myeloid immune responses in autoimmune diseases in a divergent manner. HIF‐1 drives autoimmune inflammation by controlling divergent pro/anti‐inflammatory function of different immune cells located in the inflammatory lesions.