Tonic type 2 immunity controls autoimmunity in the skin

The existence of immunoregulatory mechanisms that control autoimmunity in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we found that psoriasis is tightly associated with a significant downregulation of fatty acid metabolism and biosynthesis pathways as well as Th2 signature genes. Among lipids-activated transcription factors, LXR and PPAR were required for fatty acid homeostasis and resistance to psoriasis in mice. STAT6 played a role in the homeostatic expression of LXR and PPARγ in the skin. Additionally, innate lymphoid cells established tonic type 2 immunity in normal skin by producing IL-13 continually. Mice lacking tonic type 2 immunity were more susceptible to psoriatic inflammation in vivo. In human skin, inhibiting tonic type 2 immunity worsened psoriasis-like inflammation and IL-17 production, while activating LXR or PPAR inhibited them. Therefore, tonic type 2 immunity is an essential tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.