真武唐(ZWT),传统的草药混合物,临床上已推荐用于治疗狼疮性肾炎(LN)。然而,其作用机制仍然未知。在这里,我们旨在定义ZWT对LN的影响的免疫学机制,并确定其是否影响肾组织驻留的记忆T(TRM)细胞。鼠LN是通过单次注射普利坦诱导的,而体外TRM细胞分化为IL-15/TGF-β。我们发现ZWT或霉酚酸酯治疗可通过降低24小时尿蛋白来显着改善LN小鼠的肾损伤。Scr和抗dsDNAAb。ZWT还改善了肾脏病理并减少了IgG和C3沉积。此外,ZWT下调肾Desmin表达。此外,它降低了LN小鼠肾脏中CD8TRM细胞的数量,同时降低了TNF-α和IFN-γ的表达。与体内结果一致,含ZWT的血清在体外抑制IL-15/TGF-β诱导的TRM细胞分化。机械上,抑制CD8+TRM细胞中STAT3和CD122(IL2/IL-15Rβ)的磷酸化表达。重要的是,ZWT减少了F4/80+CD11b+和CD86+的总数,但不是CD206+,LN小鼠肾脏中的巨噬细胞。有趣的是,ZWT在体内和体外抑制巨噬细胞中IL-15蛋白的表达。因此,我们提供了第一个证据,证明ZWT汤可通过抑制IL-15/IL-15R/STAT3信号传导而减少CD8+TRM细胞,从而改善LN的预后.
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 (TRM) cells. Murine LN was induced by a single injection of pristane, while in vitro TRM 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+ TRM 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 TRM cell differentiation induced by IL-15/TGF-β in vitro. Mechanistically, it suppressed phosphorylation of STAT3 and CD122 (IL2/IL-15Rβ)expression in CD8+ TRM cells. Importantly, ZWT reduced the number of total F4/80+CD11b+ 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+ TRM cells via inhibition of IL-15/IL-15R /STAT3 signaling.