The IDO1/AhR-HIF-1α metabolic axis: ARNT competition as a central antagonistic switch in autoimmune pathogenesis.

The immunometabolic checkpoint axis formed by the IDO1/AhR pathway and the HIF-1α pathway, which functionally antagonize each other via their competition for the shared transcriptional partner aryl hydrocarbon receptor nuclear translocator (ARNT), profoundly regulates the pathogenesis and progression of autoimmune diseases. Following activation of the aryl hydrocarbon receptor (AhR) by kynurenine (Kyn), a tryptophan metabolite generated by IDO1, the activated AhR and hypoxia-induced HIF-1α intensely compete for the limited pool of ARNT protein. This competition results in the formation of two distinct transcriptional complexes: AhR/ARNT and HIF-1α/ARNT. These complexes drive opposing immune programs. The AhR/ARNT complex promotes immune tolerance by facilitating Treg cell differentiation, inducing a tolerogenic phenotype in dendritic cells, promoting M2 macrophage polarization, and sustaining the survival of long-lived plasma cells. Conversely, the HIF-1α/ARNT complex enhances glycolysis and amplifies inflammation, driving Th17 cell differentiation, activating the pro-inflammatory functions of dendritic cells, promoting M1 macrophage polarization, and stimulating plasmablast proliferation. In autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and membranous nephropathy (MN), dysregulation of this axis is characterized by excessive HIF-1α signaling and relative insufficiency of the IDO1/AhR pathway. This imbalance leads to the monopolization of ARNT by the HIF-1α pathways, consequently exacerbating Treg/Th17 imbalance, autoantibody production, and tissue damage. Targeting this axis, for instance through combined HIF-1α inhibitors and IDO1/AhR pathway agonists, holds promise as a novel metabolic intervention strategy for autoimmune diseases.