脂联素-2 通过促进 Th1 细胞分化加重狼疮肾炎。
Lipocalin-2 Exacerbates Lupus Nephritis by Promoting Th1 Cell Differentiation.
机构信息
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China.
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Model Animal Research Center of Nanjing University, Nanjing, China
出版信息
J Am Soc Nephrol. 2020 Oct;31(10):2263-2277. doi: 10.1681/ASN.2019090937. Epub 2020 Jul 9.
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/ mice and analyzing pristane-treated 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- overexpression in CD4 T cells through the IL-12/STAT4 pathway in an autocrine or paracrine manner. Both neutralization of LCN2 in MRL/ 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.
背景
脂联素-2（LCN2）是狼疮肾炎（LN）严重程度的一个指标，在免疫反应中起着关键作用，但尚不清楚其对 LN 发病机制的影响是否源于调节 T 淋巴细胞亚群的免疫失衡。
方法
通过对 LN 患者的肾活检组织评估 LCN2 在 T 细胞和肾脏中的表达，我们通过向 MRL/ 小鼠注射抗 LCN2 抗体并分析用 pristane 处理的小鼠，研究了 LCN2 水平与 LN 和全身疾病发展之间的关系。
结果
LCN2 在 CD4 T 细胞和肾脏组织中高表达，与 LN 患者和实验性狼疮小鼠的严重肾脏损伤相关。LCN2 通过自分泌或旁分泌的方式通过 IL-12/STAT4 途径促进 CD4 T 细胞中 IFN- 的过度表达。在 MRL/ 小鼠中中和 LCN2 和在 pristane 诱导的狼疮小鼠中基因耗竭 LCN2 均可显著改善肾炎。脾和肾 Th1 细胞的频率和数量与 LN 疾病活动度成比例减少。相反，LCN2 的给药会使疾病恶化，肾脏活性评分显著升高，Th1 细胞数量增加。
结论
LCN2 在 Th1 细胞分化中起关键作用，可能是 LN 的潜在治疗靶点。
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