Division of Molecular Parasitology and Immunology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Division of Biological Sciences, Academy of Scientific and Innovative Research (AcSIR), CSIR Human Resource Development Centre (CSIR-HRDC) Campus, Postal Staff College Area, Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh 201 002, India.
J Cell Sci. 2021 Mar 4;134(5):jcs252494. doi: 10.1242/jcs.252494.
Notch signaling governs crucial aspects of intercellular communication spanning antigen-presenting cells and T-cells. In this study, we investigate how takes advantage of this pathway to quell host immune responses. We report induction of the Notch ligand Jagged1 in -infected bone marrow macrophages (BMMϕs) and subsequent activation of RBPJκ (also known as RBPJ) in T cells, which in turn upregulates the transcription factor GATA3. Activated RBPJκ also associates with the histone acetyltransferase p300 (also known as EP300), which binds with the promoter and enhances its expression. Interaction of Bcl2L12 with GATA3 in CD4 T cells facilitates its binding to the interleukin (IL)-10 and IL-4 promoters, thereby increasing the secretion of these cytokines. Silencing Jagged1 hindered these events in a BMMϕ-T cell co-culture system. Upon further scrutiny, we found that parasite lipophosphoglycan (LPG) induces the host phosphoinositide 3-kinase (PI3K)/Akt pathway, which activates β-catenin and Egr1, the two transcription factors responsible for driving Jagged1 expression. morpholino-silencing of Jagged1 suppresses anti-inflammatory cytokine responses and reduces organ parasite burden in -infected Balb/c mice, suggesting that -induced host Jagged1-Notch signaling skews macrophage-T cell crosstalk into disease-promoting Th2 mode in experimental visceral leishmaniasis.This article has an associated First Person interview with the first author of the paper.
Notch 信号通路调控着抗原呈递细胞和 T 细胞之间细胞间通讯的关键方面。在这项研究中，我们研究了 如何利用这条通路来抑制宿主免疫反应。我们报告了在 感染的骨髓巨噬细胞（BMMϕ）中诱导 Notch 配体 Jagged1，以及随后在 T 细胞中激活 RBPJκ（也称为 RBPJ），这反过来又上调转录因子 GATA3。激活的 RBPJκ 还与组蛋白乙酰转移酶 p300（也称为 EP300）结合，后者与 启动子结合并增强其表达。在 CD4 T 细胞中，Bcl2L12 与 GATA3 的相互作用促进其与白细胞介素（IL）-10 和 IL-4 启动子结合，从而增加这些细胞因子的分泌。沉默 Jagged1 会在 BMMϕ-T 细胞共培养系统中阻碍这些事件的发生。进一步研究发现，寄生虫脂磷壁酸（LPG）诱导宿主磷酯酰肌醇 3-激酶（PI3K）/Akt 通路，该通路激活β-catenin 和 Egr1，这两个转录因子负责驱动 Jagged1 的表达。Jagged1 的 基因敲低抑制了抗炎细胞因子的反应，并减少了感染 的 Balb/c 小鼠中的器官寄生虫负担，这表明 诱导的宿主 Jagged1-Notch 信号通路将巨噬细胞-T 细胞串扰偏向于实验性内脏利什曼病中的促病 Th2 模式。本文有该论文第一作者的相关第一人称采访。
