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旋毛虫二肽基肽酶 1 可通过 STAT6/PPARγ 通路促进 M2 极化来抑制巨噬细胞的细胞毒性。

Trichinella spiralis dipeptidyl peptidase 1 suppressed macrophage cytotoxicity by promoting M2 polarization via the STAT6/PPARγ pathway.

机构信息

Department of Parasitology, Medical College, Zhengzhou University, Zhengzhou, 450052, China.

出版信息

Vet Res. 2023 Sep 13;54(1):77. doi: 10.1186/s13567-023-01209-2.

DOI:10.1186/s13567-023-01209-2
PMID:37705099
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10500742/
Abstract

Trichinella spiralis dipeptidyl peptidase 1 (TsDPP1), or cysteine cathepsin C, is a secretory protein that is highly expressed during the infective larvae and adult worm stages in the intestines. The aim of this study was to investigate the mechanism by which recombinant TsDPP1 (rTsDPP1) activates macrophages M2 polarization and decreases macrophage cytotoxicity to kill newborn larvae via ADCC. RAW264.7 macrophages and murine peritoneal macrophages were used in this study. The results of the immunofluorescence test (IFT) and confocal microscopy showed that rTsDPP1 specifically bound to macrophages, and the binding site was localized on the cell membrane. rTsDPP1 activated macrophage M2 polarization, as demonstrated by high expression levels of Arg1 (M2 marker) and M2-related genes (IL-10, TGF-β, CD206 and Arg1) and high numbers of CD206 macrophages. Furthermore, the expression levels of p-STAT6, STAT6 and PPARγ were obviously increased in rTsDPP1-treated macrophages, which were evidently abrogated by using a STAT6 inhibitor (AS1517499) and PPARγ antagonist (GW9662). The results indicated that rTsDPP1 promoted macrophage M2 polarization through the STAT6/PPARγ pathway. Griess reaction results revealed that rTsDPP1 suppressed LPS-induced NO production in macrophages. qPCR and flow cytometry results showed that rTsDPP1 downregulated the expression of FcγR I (CD64) in macrophages. The ability of ADCC to kill newborn larvae was significantly decreased in rTsDPP1-treated macrophages, but AS1517499 and GW9662 restored its killing capacity. Our results demonstrated that rTsDPP1 induced macrophage M2 polarization, upregulated the expression of anti-inflammatory cytokines, and inhibited macrophage-mediated ADCC via activation of the STAT6/PPARγ pathway, which is beneficial to the parasitism and immune evasion of this nematode.

摘要

旋毛虫二肽基肽酶 1（TsDPP1）或半胱氨酸组织蛋白酶 C，是一种分泌蛋白，在感染性幼虫和成虫阶段在肠道中高度表达。本研究旨在探讨重组 TsDPP1（rTsDPP1）通过 ADCC 激活巨噬细胞 M2 极化并降低巨噬细胞细胞毒性以杀死新生幼虫的机制。本研究使用 RAW264.7 巨噬细胞和鼠腹腔巨噬细胞。免疫荧光试验（IFT）和共聚焦显微镜的结果表明，rTsDPP1特异性结合巨噬细胞，结合部位定位于细胞膜上。rTsDPP1 激活了巨噬细胞 M2 极化，表现为 Arg1（M2 标志物）和 M2 相关基因（IL-10、TGF-β、CD206 和 Arg1）的高表达以及 CD206 巨噬细胞的高数量。此外，rTsDPP1 处理的巨噬细胞中 p-STAT6、STAT6 和 PPARγ 的表达水平明显增加，而使用 STAT6 抑制剂（AS1517499）和 PPARγ 拮抗剂（GW9662）则明显阻断了这些表达。结果表明，rTsDPP1 通过 STAT6/PPARγ 通路促进巨噬细胞 M2 极化。格里斯反应结果表明，rTsDPP1 抑制巨噬细胞中 LPS 诱导的 NO 产生。qPCR 和流式细胞术结果表明，rTsDPP1 下调巨噬细胞中 FcγR I（CD64）的表达。rTsDPP1 处理的巨噬细胞中 ADCC 杀死新生幼虫的能力显著降低，但 AS1517499 和 GW9662 恢复了其杀伤能力。我们的结果表明，rTsDPP1 通过激活 STAT6/PPARγ 通路诱导巨噬细胞 M2 极化，上调抗炎细胞因子的表达，并抑制巨噬细胞介导的 ADCC，这有利于这种线虫的寄生和免疫逃避。

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