Anti-PS IgG Immune Complexes Impair Macrophage Phagocytosis in SLE via LOX-Dependent Oxidative Stress

  • J Inflamm Res. 2025 Aug 22:18:11521-11538. doi: 10.2147/JIR.S527859.
Hui Guan  #  1  2  3 ,  Liqi Huang  #  1 ,  Yu Liu  #  1 ,  Enyi Zhu  4 ,  Lefeng Chen  5 ,  Weijie Li  2 ,  Haiqi Wu  2 ,  Xiaoying Zhang  6 ,  Rencai Qin  2 ,  Jingpeng Zheng  2 ,  Yingqian Mo  5 ,  Ming Zhong  1 ,  Bihua Xu  7 ,  Xiaoyan Dai  8 ,  Qi Wei  2 ,  Yunwei Chen  2 ,  Qingwen Wang  7 ,  Zhihua Zheng  1 ,  Kongyang Ma  2 ,  Chun Tang  1
Affiliations
  • 1. Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
  • 2. Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, 518107, People's Republic of China.
  • 3. Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
  • 4. The Division of Nephrology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, 510000, People's Republic of China.
  • 5. Department of Rheumatology, Sun Yat-sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, People's Republic of China.
  • 6. Health Management Center, the Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
  • 7. Department of Rheumatology and Immunology, Peking University Shenzhen Hospital, Shenzhen, 518036, People's Republic of China.
  • 8. Clinical Research Institute, Hengyang Medical School, the second Affiliated Hospital, University of South China, Hengyang, 421002, People's Republic of China.
  • # Contributed equally.
PMID: 40873781 DOI: 10.2147/JIR.S527859
Abstract

Purpose: Systemic Lupus Erythematosus (SLE) is a severe Autoimmune Disease with systemic complications mediated by immune-complex formation. The elevated level of anti-phosphatidylserine (PS) IgG has been implicated in SLE pathogenesis. In this study, we aimed to explore the effector mechanisms of PS immune-complex during lupus development.

Patients and methods: Serological profiles of immune-complexes in SLE patients were analyzed. Immunofluorescence staining showed PS-IgG immune-complex deposition in kidney biopsies of lupus Nephritis patients. C57BL/6J mice were immunized with PS for immune-complex and renal function assessment. The roles of PS-IgG immune-complex and Lysyl Oxidase (LOX) were validated from SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. The intracellular reactive oxygen species (ROS) levels, and phagocytosis function were examined by flow cytometry in SLE PBMCs, THP-1 cell line and PS-immunized lupus mice. For in vitro treatment, the effects of antioxidant N-acetylcysteine (NAC) and LOX inhibitor β-Aminopropionitrile (BAPN) were verified in THP-1 cell line and cells from PS-immunized lupus mice.

Results: SLE and lupus Nephritis (LN) patients showed significant elevated circulating and glomerular PS-IgG immune-complex levels. ROC analysis indicated PS-IgG immune-complex as a strong biomarker in SLE and LN. Mechanistically, induced Macrophages from SLE patients treated with PS-IgG immune-complex significantly increased cytoplasmic ROS levels, elevated LOX expression and exhibited dampened phagocytotic function. In mice, PS immunization triggered PS-IgG immune complex formation, increased LOX expression, immune-complex deposited glomerular Nephritis, and impaired phagocytotic function of Macrophages. NAC and BAPN treatment restored the phagocytotic function of human and murine Macrophages.

Conclusion: Our results indicate that PS-IgG immune-complex can directly impair macrophage phagocytotic functions via LOX mediated-oxidative stress and may serve as a novel biomarker for SLE.

Keywords
anti-phospholipid antibodies; immune complex; macrophages; systemic lupus erythematosus.
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