2. Academic Validation
  3. Tonic type 2 immunity is a critical tissue checkpoint controlling autoimmunity in the skin

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

  • Cell Rep. 2024 Jun 18;43(7):114364. doi: 10.1016/j.celrep.2024.114364.
Jeong-Eun Lee 1,  Mina Kim 1,  Sotaro Ochiai 2,  Sung-Hee Kim 3,  Hyeonuk Yeo 1,  Jahyun Bok 1,  Jiyeon Kim 1,  Miso Park 4,  Daehong Kim 1,  Olivier Lamiable 2,  Myunggyo Lee 5,  Min-Ju Kim 5,  Hye Young Kim 6,  Franca Ronchese 7,  Sung Won Kwon 8,  Haeseung Lee 9,  Tae-Gyun Kim 10,  Yeonseok Chung 11
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
  • 2 Malaghan Institute of Medical Research, Wellington, New Zealand.
  • 3 Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 4 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.
  • 5 College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea.
  • 6 College of Medicine, Seoul National University, Seoul, Republic of Korea.
  • 7 Malaghan Institute of Medical Research, Wellington, New Zealand. Electronic address: fronchese@malaghan.org.nz.
  • 8 Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea. Electronic address: swkwon@snu.ac.kr.
  • 9 College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea. Electronic address: haeseung@pusan.ac.kr.
  • 10 Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: tgmed83@yuhs.ac.
  • 11 Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Republic of Korea. Electronic address: yeonseok@snu.ac.kr.
PMID: 38900635 DOI: 10.1016/j.celrep.2024.114364
Abstract

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.

Keywords

CP: Immunology; LXR; PPARγ; fatty acid metabolism; psoriasis; tonic type 2 immunity.

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