Roy Shalini, Gupta Purnima, Palit Shreyasi, Basu Moumita, Ukil Anindita, Das Pijush K
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India.
Department of Biochemistry, Calcutta University, Kolkata, India.
Clin Transl Immunology. 2017 May 5;6(5):e137. doi: 10.1038/cti.2017.12. eCollection 2017 May.
Programmed death-1 receptor (PD-1) expressed in many immune cells is known to trigger T-cell exhaustion but the significance of macrophage-associated PD-1 in relevance to macrophage apoptosis is not known. This study is aimed to delineate whether PD-1 pathway has any role in eliciting macrophage apoptosis and, if so, then how the intra-macrophage parasite, modulates PD-1 pathway for protecting its niche. Resting macrophages when treated with HO showed increased PD-1 expression and apoptosis, which was further enhanced on PD-1 agonist treatment. The administration of either PD-1 receptor or PD-1 ligand-blocking antibodies reversed the process thus documenting the involvement of PD-1 in macrophage apoptosis. On the contrary, -infected macrophages showed decreased PD-1 expression concurrent with inhibition of apoptosis. The activation of PD-1 pathway was found to negatively regulate the phosphorylation of pro-survival AKT, which was reversed during infection. Infection-induced PD-1 downregulation led to the activation of AKT resulting in phosphorylation and subsequent inhibition of proapoptotic protein BAD. Strong association of SHP2 (a SH2-containing ubiquitously expressed tyrosine-specific protein phosphatase) with PD-1 along with AKT deactivation observed in HO-treated macrophages was reversed by infection. Kinetic analysis coupled with inhibitor-based approach and knockdown experiments demonstrated that . infection actively downregulated the PD-1 by deactivating NFATc1 as revealed by its reduced nuclear translocation. The study thus elucidates the detailed mechanism of the role of PD-1 in macrophage apoptosis and its negative modulation by for their intracellular survival.
已知在许多免疫细胞中表达的程序性死亡-1受体（PD-1）会引发T细胞耗竭，但巨噬细胞相关的PD-1与巨噬细胞凋亡相关性的意义尚不清楚。本研究旨在阐明PD-1通路在引发巨噬细胞凋亡中是否起作用，如果是，那么巨噬细胞内的寄生虫如何调节PD-1通路以保护其生存环境。静息巨噬细胞用HO处理后，PD-1表达和凋亡增加，PD-1激动剂处理后进一步增强。给予PD-1受体或PD-1配体阻断抗体可逆转这一过程，从而证明PD-1参与巨噬细胞凋亡。相反，感染巨噬细胞显示PD-1表达降低，同时凋亡受到抑制。发现PD-1通路的激活负向调节促生存AKT的磷酸化，感染期间这种调节作用被逆转。感染诱导的PD-1下调导致AKT激活，从而导致促凋亡蛋白BAD的磷酸化及随后的抑制。在HO处理的巨噬细胞中观察到的SHP2（一种含SH2的普遍表达的酪氨酸特异性蛋白磷酸酶）与PD-1的强关联以及AKT失活，在感染后被逆转。动力学分析结合基于抑制剂的方法和敲低实验表明，感染通过使NFATc1失活而积极下调PD-1，这可通过其核转位减少来揭示。因此，该研究阐明了PD-1在巨噬细胞凋亡中的作用及其被感染负向调节以实现细胞内存活的详细机制。
