Tonic type 2 immunity is a critical tissue checkpoint controlling autoimmunity in the skin

초록

Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non -lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPAR g ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPAR g. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4R a ), or IL -13, but not IL -4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL -13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis -like inflammation and IL -17A, while activating LXR or PPAR g inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL -13 -producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.

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