2. Academic Validation
  3. Induction of LY6E regulates interleukin-1β production, potentially contributing to the immunopathogenesis of systemic lupus erythematosus

Induction of LY6E regulates interleukin-1β production, potentially contributing to the immunopathogenesis of systemic lupus erythematosus

  • Cell Commun Signal. 2025 Mar 20;23(1):146. doi: 10.1186/s12964-025-02140-z.
Jenn-Haung Lai 1,  De-Wei Wu 2,  Chuan-Yueh Huang 3,  Li-Feng Hung 3,  Chien-Hsiang Wu 2,  Shuk-Man Ka 4,  Ann Chen 5,  Jing-Long Huang 6 7,  Ling-Jun Ho 8
Affiliations

Affiliations

  • 1 Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan, ROC. laiandho@gmail.com.
  • 2 Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan, ROC.
  • 3 Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, ROC.
  • 4 Graduate Institute of Aerospace and Undersea Medicine, Department of Medicine, National Defense Medical Center, Taipei, Taiwan, ROC.
  • 5 Department of Pathology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, ROC.
  • 6 Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan , 333, Taiwan, ROC.
  • 7 Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei City , 236, Taiwan, ROC.
  • 8 Institute of Cellular and System Medicine, National Health Research Institute, Zhunan, Taiwan, ROC. lingjunho@nhri.org.tw.
PMID: 40114200 DOI: 10.1186/s12964-025-02140-z
Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the deposition of immune complexes (ICs) in various organs, especially the kidney, leading to lupus nephritis, one of the major and therapeutically challenging manifestations of SLE. Among the various cytokines induced in SLE, type I interferons (IFN-Is) play crucial roles in mediating immunopathogenesis, and anti-IFN-I treatment has been approved for SLE treatment. The uptake of ICs by macrophages results in macrophage activation, which initiates, triggers, and exaggerates immune responses in SLE. After observing the induction of an IFN-stimulated gene, LY6E, in monocytes from SLE patients, we demonstrated the colocalization of both LY6E and a macrophage marker in kidneys from pristane-induced lupus-prone mice and from patients with lupus nephritis. By studying mouse bone marrow-derived macrophages, we showed that LY6E regulated IFN-α- and IC-induced production and secretion of mature interleukin-1β (mIL-1β), foam cell formation and several mitochondria-associated mechanisms, such as the release of mitochondrial DNA (mtDNA) but not mitochondrial RNA (mtRNA) into the cytosol, the generation of mitochondrial Reactive Oxygen Species (mtROS) and ROS, the activation of Caspase 1, NLRP3, and the stimulator of interferon genes (STING) signaling pathway, and the activation of cytidine/uridine monophosphate kinase 2 (CMPK2), which were involved in LY6E-mediated immunomodulatory effects. In addition, synergistic effects of a combination of IL-1β and IFN-α and of IL-1β and ICs on the induction of the expression of IFN-stimulated genes were observed. In addition to revealing the proinflammatory roles and mechanisms of LY6E in macrophages, given that various subgroups of macrophages have been identified in the kidneys of patients with lupus nephritis, targeted treatment aimed at LY6E may be a potential therapeutic for lupus nephritis.

Keywords

Interferon-alpha; Interleukin-1; LY6E; Lupus nephritis; Macrophages; Systemic lupus erythematosus.

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