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  3. The Oxysterol Receptor EBI2 Links Innate and Adaptive Immunity to Limit IFN Response and Systemic Lupus Erythematosus

The Oxysterol Receptor EBI2 Links Innate and Adaptive Immunity to Limit IFN Response and Systemic Lupus Erythematosus

  • Adv Sci (Weinh). 2023 Jul 19;e2207108. doi: 10.1002/advs.202207108.
Fang Zhang 1 2 3,  Baokai Zhang 1 2,  Huihua Ding 4,  Xiangyue Li 1 2,  Xilin Wang 1 2,  Xiaomin Zhang 5,  Qiaojie Liu 5,  Qiuyun Feng 1 2,  Mingshun Han 6,  Longlong Chen 7 8,  Linlin Qi 1 2,  Dan Yang 5,  Xiaojing Li 1 2,  Xingguo Zhu 1 2,  Qi Zhao 1 2,  Jiaqian Qiu 9,  Zhengjiang Zhu 9,  Huiru Tang 7 8,  Nan Shen 4,  Hongyan Wang 6 10,  Bin Wei 1 2 3 5 11
Affiliations

Affiliations

  • 1 Institute of Geriatrics, Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.
  • 2 Immune Cells and Human Diseases Lab, Shanghai Engineering Research Center of Organ Repair, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
  • 3 Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
  • 4 Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200127, China.
  • 5 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, University of Chinese Academy of Science, Wuhan, 430071, China.
  • 6 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
  • 7 State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 8 Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Fudan University, Shanghai, 200032, China.
  • 9 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China.
  • 10 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 11 Department of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Key Laboratory of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350000, China.
PMID: 37469011 DOI: 10.1002/advs.202207108
Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with abnormal activation of the immune system. Recent attention is increasing about how aberrant lipid and Cholesterol metabolism is linked together with type I interferon (IFN-I) signaling in the regulation of the pathogenesis of SLE. Here, a metabonomic analysis is performed and increased plasma concentrations of oxysterols, especially 7α, 25-dihydroxycholesterol (7α, 25-OHC), are identified in SLE patients. The authors find that 7α, 25-OHC binding to its receptor Epstein-Barr virus-induced gene 2 (EBI2) in macrophages can suppress STAT activation and the production of IFN-β, chemokines, and cytokines. Importantly, monocytes/macrophages from SLE patients and mice show significantly reduced EBI2 expression, which can be triggered by IFN-γ produced in activated T cells. Previous findings suggest that EBI2 enhances immune cell migration. Opposite to this effect, the authors demonstrate that EBI2-deficient macrophages produce higher levels of chemokines and cytokines, which recruits and activates myeloid cells,T and B lymphocytes to exacerbate tetramethylpentadecane-induced SLE. Together, via sensing the oxysterol 7α, 25-OHC, EBI2 in macrophages can modulate innate and adaptive immune responses, which may be used as a potential diagnostic marker and therapeutic target for SLE.

Keywords

Epstein-Barr virus-induced gene 2; interferon; macrophages; oxysterols; systemic lupus erythematosus.

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