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Differential Induction of SOCS Isoforms by Leishmania donovani Impairs Macrophage–T Cell Cross-Talk and Host Defense
The Journal of Immunology ( IF 4.4 ) Pub Date : 2019-12-27 , DOI: 10.4049/jimmunol.1900412
Pragya Chandrakar 1, 2 , Naveen Parmar 1, 2 , Albert Descoteaux 3 , Susanta Kar 2, 4
Affiliation  

Key Points L. donovani induces SOCS1 in BMMфs by PI3K/Akt/Egr2 and IDO/kynurenine pathway. PGE2 from infected BMMфs activates cAMP/PKA-mediated SOCS3 expression in T cells. This inhibited STAT1- and STAT4-mediated IFN-γ and IL-12 synthesis in immune cells. Immune evasion strategies adopted by Leishmania donovani involve the exploitation of suppressor of cytokine signaling (SOCS) proteins that are well-known negative regulators of the JAK/STAT pathway. However, the cellular mechanism underpinning the induction of SOCS isoforms and their role in breaching the multilevel regulatory circuit connecting the innate and adaptive arms of immunity are still ambiguous during experimental visceral leishmaniasis. Using bone marrow–derived macrophages (BMMфs) and CD4+ T cells, we observed that L. donovani preferentially upregulates SOCS1 and SOCS3 expression in macrophages and T cells, respectively, whereas the SOCS1 level remains consistently high in BMMфs and SOCS3 expression is pronounced and long lasting in T cells. Consequently, this inhibits STAT1-mediated IL-12 induction in macrophages & STAT4-mediated IFN-γ synthesis in T cells. Mechanistically, PI3K/Akt–mediated SRF activation promotes nuclear translocation and binding of Egr2 to SOCS1 promoter for its early induction in infected BMMфs. Additionally, L. donovani activates IDO/kynurenine/AHR signaling in BMMфs to maintain prolonged SOCS1 expression. Later, PGE2, secreted from infected BMMфs induces cAMP–PKA pathway by binding to the EP2/EP4 receptor of CD4+ T cells, leading to SP1, CREB, and GATA1 activation and SOCS3 expression. Small interfering RNA–mediated silencing of SOCS1 and SOCS3 in macrophage and T cells, respectively, restored IL-12 and IFN-γ cytokine levels and BMMф–T cell interaction. Vivo morpholino–mediated silencing of SOCS1 and SOCS3 resulted in protective cytokine responses, thereby reducing organ parasite burden significantly in L. donovani–infected BALB/c mice. Collectively, our results imply that L. donovani orchestrates different SOCS isoforms to impair macrophage–T cell cross-talk and preserve its own niche.

中文翻译:

多诺瓦利什曼原虫对 SOCS 同种型的差异诱导损害巨噬细胞-T 细胞串扰和宿主防御

关键点 L. donovani 通过 PI3K/Akt/Egr2 和 IDO/犬尿氨酸途径诱导 BMMфs 中的 SOCS1。来自受感染 BMMфs 的 PGE2 激活 T 细胞中 cAMP/PKA 介导的 SOCS3 表达。这抑制了免疫细胞中 STAT1 和 STAT4 介导的 IFN-γ 和 IL-12 合成。多诺瓦利什曼原虫采用的免疫逃避策略涉及利用细胞因子信号抑制因子 (SOCS) 蛋白,这些蛋白是众所周知的 JAK/STAT 通路负调节因子。然而,在实验性内脏利什曼病期间,支持 SOCS 同种型诱导的细胞机制及其在破坏连接先天性和适应性免疫臂的多级调节回路中的作用仍然不明确。使用骨髓来源的巨噬细胞 (BMMфs) 和 CD4+ T 细胞,我们观察到 L. donovani 分别优先上调巨噬细胞和 T 细胞中 SOCS1 和 SOCS3 的表达,而 SOCS1 水平在 BMMфs 中始终保持高水平,而 SOCS3 表达在 T 细胞中显着且持久。因此,这会抑制巨噬细胞中 STAT1 介导的 IL-12 诱导和 T 细胞中 STAT4 介导的 IFN-γ 合成。从机制上讲,PI3K/Akt 介导的 SRF 激活促进核易位和 Egr2 与 SOCS1 启动子的结合,以促进其在受感染的 BMMфs 中的早期诱导。此外,L. donovani 激活 BMMфs 中的 IDO/犬尿氨酸/AHR 信号以维持延长的 SOCS1 表达。后来,从受感染的 BMMфs 分泌的 PGE2 通过与 CD4+ T 细胞的 EP2/EP4 受体结合诱导 cAMP-PKA 通路,导致 SP1、CREB ​​和 GATA1 激活和 SOCS3 表达。分别在巨噬细胞和 T 细胞中小干扰 RNA 介导的 SOCS1 和 SOCS3 沉默恢复了 IL-12 和 IFN-γ 细胞因子水平以及 BMMф-T 细胞相互作用。体内吗啉代介导的 SOCS1 和 SOCS3 沉默导致保护性细胞因子反应,从而显着降低了杜氏乳杆菌感染的 BALB/c 小鼠的器官寄生虫负担。总的来说,我们的结果意味着 L. donovani 协调不同的 SOCS 亚型来削弱巨噬细胞-T 细胞的串扰并保留其自身的生态位。
更新日期:2019-12-27
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