Tonic type 2 immunity is a critical tissue checkpoint controlling autoimmunity in the skin
Jeong-Eun Lee,
Mina Kim,
Sotaro Ochiai,
Sung-Hee Kim,
Hyeonuk Yeo,
Jahyun Bok,
Jiyeon Kim,
Miso Park,
Daehong Kim,
Olivier Lamiable,
Myunggyo Lee,
Min-Ju Kim,
Hye Young Kim,
Franca Ronchese,
Sung Won Kwon,
Haeseung Lee,
Tae-Gyun Kim,
Yeonseok Chung
Affiliations
Jeong-Eun Lee
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Mina Kim
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Sotaro Ochiai
Malaghan Institute of Medical Research, Wellington, New Zealand
Sung-Hee Kim
Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
Hyeonuk Yeo
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Jahyun Bok
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Jiyeon Kim
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Miso Park
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea; College of Pharmacy, Kangwon National University, Chuncheon, Republic of Korea
Daehong Kim
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea
Olivier Lamiable
Malaghan Institute of Medical Research, Wellington, New Zealand
Myunggyo Lee
College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
Min-Ju Kim
College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
Hye Young Kim
College of Medicine, Seoul National University, Seoul, Republic of Korea
Franca Ronchese
Malaghan Institute of Medical Research, Wellington, New Zealand; Corresponding author
Sung Won Kwon
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Corresponding author
Haeseung Lee
College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea; Corresponding author
Tae-Gyun Kim
Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Corresponding author
Yeonseok Chung
Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea; Corresponding author
Summary: 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.
