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

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114364
• Main Authors: Lee, Jeong-Eun, Kim, Mina, Ochiai, Sotaro, Kim, Sung-Hee, Yeo, Hyeonuk, Bok, Jahyun, Kim, Jiyeon, Park, Miso, Kim, Daehong, Lamiable, Olivier, Lee, Myunggyo, Kim, Min-Ju, Kim, Hye Young, Ronchese, Franca, Kwon, Sung Won, Lee, Haeseung, Kim, Tae-Gyun, Chung, Yeonseok
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2024; Elsevier
• Subjects: CP: Immunology; fatty acid metabolism; LXR; PPARγ; psoriasis; tonic type 2 immunity; CP: Immunology; tonic type 2 immunity; fatty acid metabolism; psoriasis; PPARγ; LXR
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114364

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 (PPARγ) 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 PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), 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 PPARγ 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. [Display omitted] •Psoriasis induces a downregulation of fatty acid metabolism and Th2 signature genes•LXR and PPARγ are required for the resistance to psoriasis and lipid homeostasis•IL-13-producing ILCs are responsible for tonic type 2 immunity in normal skin•Inhibiting tonic type 2 immunity worsens psoriatic inflammation in mice and humans Lee et al. show that fatty acid dysregulation occurs in psoriatic skin. Lack of LXR or PPARγ exacerbates psoriasis progression, and LXR and PPARγ homeostasis is maintained by tonic type 2 immunity. IL-13-producing ILCs are in charge of tonic type 2 immunity and contribute to the resistance to autoimmunity.