Mechanisms of interferon-beta-induced inhibition of Toxoplasma gondii growth in murine macrophages and embryonic fibroblasts: role of immunity-related GTPase M1
Mechanisms of interferon-beta-induced inhibition of Toxoplasma gondii growth in murine macrophages and embryonic fibroblasts: role of immunity-related GTPase M1
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DOI：
10.1111/cmi.12423
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发表时间：
2015-07-01
影响因子：
3.4
通讯作者：
Nishikawa, Yoshifumi
中科院分区：
文献类型：
--
作者：
Mahmoud, Motamed Elsayed;Ui, Fumiki;Nishikawa, Yoshifumi
刚地弓形虫的根尖复合体使它能够侵入包括人类在内的温血动物的几乎所有有核细胞，使它成为一种具有全球重要性的寄生虫。Anti-T。弓形虫的细胞防御机制主要依赖于免疫细胞产生干扰素（IFN）。然而，IFN介导的防御的分子机制在很大程度上仍不清楚。在这里，小鼠腹膜巨噬细胞和小鼠胚胎成纤维细胞（MEFs）被重组IFN-和IFN-激活，显示出不同的激活途径。用IFN-或IFN-处理这些细胞可抑制弓形虫（II型PLK菌株）的生长。IFN-对巨噬细胞炎性细胞因子表达、诱导型一氧化氮合酶和吲哚胺2,3-双加氧酶均无影响，对其代谢产物一氧化氮和犬尿氨酸均无影响。相比之下，IFN-刺激的特征是经典的巨噬细胞激活和弓形虫消除。IFN-激活将免疫相关的GTPase M1 （IRGM1）募集到巨噬细胞和mef的寄生液泡中。IRGM1敲除小鼠巨噬细胞和IRGM1缺失mef后，IFN-诱导的抗弓形虫活性显著降低。因此，本研究揭示了IFN-激活巨噬细胞的另一种途径，并为IFN-诱导的IRGM1在消除弓形虫中的作用提供了机制解释。
The apical complex of Toxoplasma gondii enables it to invade virtually all nucleated cells in warm-blooded animals, including humans, making it a parasite of global importance. Anti-T.gondii cellular defence mechanisms depend largely on interferon (IFN)- production by immune cells. However, the molecular mechanism of IFN--mediated defence remains largely unclear. Here, mouse peritoneal macrophages and murine embryonic fibroblasts (MEFs) primed with recombinant IFN- and IFN- showed different pathways of activation. Treatment of these cells with IFN- or IFN- inhibited T.gondii (type II PLK strain) growth. Priming macrophages with IFN- had no effect on inflammatory cytokine expression, inducible nitric oxide synthase or indoleamine 2,3-dioxygenase, nor did it have an effect on their metabolites, nitric oxide and kynurenine respectively. In contrast, IFN- stimulation was characterized by classical macrophage activation and T.gondii elimination. IFN- activation recruited the immunity-related GTPase M1 (IRGM1) to the parasitophorous vacuole in the macrophages and MEFs. Anti-toxoplasma activities induced by IFN- were significantly reduced after IRGM1 knockdown in murine macrophages and in IRGM1-deficient MEFs. Thus, this study unravels an alternative pathway of macrophage activation by IFN- and provides a mechanistic explanation for the contribution of IRGM1 induced by IFN- to the elimination of T.gondii.