Weiwei Chen1, Wenchao Li2, Zhuoya Zhang1, Xiaojun Tang1, Shufang Wu1, Genhong Yao1, Kang Li2, Dandan Wang1, Yuemei Xu3, Ruihai Feng1, Xiaoxiao Duan1, Xiangshan Fan3, Liwei Lu4, WanJun Chen5, Chaojun Li2,6, Lingyun Sun2,6. 1. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China. 2. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China licj@nju.edu.cn lingyunsun@nju.edu.cn. 3. Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China. 4. Department of Pathology, Center of Infection and Immunology, University of Hong Kong, Hong Kong, China. 5. Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland. 6. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
Abstract
BACKGROUND: Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. METHODS: The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lpr mice and analyzing pristane-treated LCN2 -/- mice. RESULTS: LCN2 is highly expressed in CD4+ T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-γ overexpression in CD4+ T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. CONCLUSIONS: LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.
BACKGROUND:Lipocalin-2 (LCN2) is an indicator of the severity of lupus nephritis (LN) and plays a pivotal role in immune responses, but it is not known if its effect on LN pathogenesis derives from regulating the immune imbalance of T lymphocyte subsets. METHODS: The expression of LCN2 in T cells and kidneys was assessed in renal biopsies from patients with LN. We investigated the relationship between LCN2 levels and development of LN and systemic illness by injecting anti-LCN2 antibodies into MRL/lpr mice and analyzing pristane-treated LCN2 -/- mice. RESULTS:LCN2 is highly expressed in CD4+ T cells and in renal tissues, and is associated with severe renal damage in patients with LN and in mice with experimental lupus. LCN2 promotes IFN-γ overexpression in CD4+ T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/lpr mice and genetic depletion of LCN2 in pristane-induced lupus mice greatly ameliorate nephritis. The frequency and number of splenic and renal Th1 cells decrease in proportion to LN disease activity. Conversely, administration of LCN2 exacerbates the disease with significantly higher renal activity scores and increased numbers of Th1 cells. CONCLUSIONS:LCN2 plays a crucial role in Th1 cell differentiation, and may present a potential therapeutic target for LN.
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