All-trans retinoic acid suppresses systemic inflammation induced by severe fever with thrombocytopenia syndrome virus in mice

Abstract

The vitamin A metabolite all-trans retinoic acid (ATRA) has immunoregulatory features, but its systemic role during viral infection is unclear. Here we show that patients infected with severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne infection, have depleted serum vitamin A and ATRA levels. This correlated with exacerbated systemic inflammatory response syndrome severity and mortality risk. In an SFTSV mouse model, intraperitoneal administration of ATRA suppresses virus-induced hyperinflammation via peroxisome proliferator-activated receptor-γ (PPARγ), which downregulates the transcriptional activity of activator protein-1 (AP-1 in macrophages. Mechanistically, ATRA binds retinoid X receptor-α (RXRα) and facilitates the formation of RXRα–PPARγ heterodimers. This complex sequesters the transcription factor JUN and suppresses the expression of AP-1 promoter-dependent genes, such as IL-6, thus attenuating inflammatory signalling pathways. Our study suggests a retinoid-mediated immunometabolic checkpoint during SFTSV infection and proposes retinoid signalling as a therapeutic target for cytokine storm management. Depletion of the vitamin A metabolite all-trans retinoic acid (ATRA) in patients infected with severe fever with thrombocytopenia syndrome virus correlates with severe inflammation. In mice, ATRA supplementation reduces IL-6 levels and hyperinflammation.