Joint Immunology Program, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
Joint Immunology Program, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China.
Biomed Pharmacother. 2024 May;174:116597. doi: 10.1016/j.biopha.2024.116597. Epub 2024 Apr 20.
Zhen-Wu-Tang (ZWT), a conventional herbal mixture, has been recommended for treating lupus nephritis (LN) in clinic. However, its mechanisms of action remain unknown. Here we aimed to define the immunological mechanisms underlying the effects of ZWT on LN and to determine whether it affects renal tissue-resident memory T (T) cells. Murine LN was induced by a single injection of pristane, while in vitro T cells differentiated with IL-15/TGF-β. We found that ZWT or mycophenolate mofetil treatment significantly ameliorated kidney injury in LN mice by decreasing 24-h urine protein, Scr and anti-dsDNA Ab. ZWT also improved renal pathology and decreased IgG and C3 depositions. In addition, ZWT down-regulated renal Desmin expression. Moreover, it lowered the numbers of CD8 T cells in kidney of mice with LN while decreasing their expression of TNF-α and IFN-γ. Consistent with in vivo results, ZWT-containing serum inhibited T cell differentiation induced by IL-15/TGF-β in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 （IL2/IL-15Rβ）expression in CD8 T cells. Importantly, ZWT reduced the number of total F4/80CD11b and CD86, but not CD206, macrophages in the kidney of LN mice. Interestingly, ZWT suppressed IL-15 protein expression in macrophages in vivo and in vitro. Thus, we have provided the first evidence that ZWT decoction can be used to improve the outcome of LN by reducing CD8 T cells via inhibition of IL-15/IL-15R /STAT3 signaling.
真武汤（ZWT）是一种传统的中草药混合物，临床上已推荐用于治疗狼疮肾炎（LN）。然而，其作用机制尚不清楚。在这里，我们旨在确定 ZWT 对 LN 的作用的免疫学机制，并确定它是否影响肾脏组织驻留记忆 T（T）细胞。通过单次注射降植烷诱导小鼠 LN，同时用 IL-15/TGF-β 体外诱导 T 细胞分化。我们发现 ZWT 或霉酚酸酯治疗可通过降低 24 小时尿蛋白、Scr 和抗 dsDNA Ab 显著改善 LN 小鼠的肾脏损伤。ZWT 还改善了肾脏病理，减少了 IgG 和 C3 的沉积。此外，ZWT 下调了肾脏 Desmin 的表达。此外，它降低了 LN 小鼠肾脏中 CD8 T 细胞的数量，同时降低了它们 TNF-α 和 IFN-γ 的表达。与体内结果一致，含 ZWT 的血清抑制了体外由 IL-15/TGF-β 诱导的 T 细胞分化。在机制上，它抑制了 CD8 T 细胞中 STAT3 和 CD122（IL2/IL-15Rβ）表达的磷酸化。重要的是，ZWT 减少了 LN 小鼠肾脏中总 F4/80CD11b 和 CD86 的数量，但不影响 CD206 巨噬细胞。有趣的是，ZWT 抑制了体内和体外巨噬细胞中 IL-15 蛋白的表达。因此，我们首次提供了证据，表明 ZWT 汤可以通过抑制 IL-15/IL-15R/STAT3 信号通路减少 CD8 T 细胞来改善 LN 的预后。
