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RIPK1 在 SMAC 模拟物诱导原发性人感染 HIV 巨噬细胞凋亡中的作用。

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages.

机构信息

Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

Division of Virology, Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Research Building 2, University of Ottawa, Ottawa, ON, K1H 8L1, Canada.

出版信息

Sci Rep. 2021 Nov 25;11(1):22901. doi: 10.1038/s41598-021-02146-w.

DOI:10.1038/s41598-021-02146-w
PMID:34824340
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8617210/
Abstract

Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC) mimetics (SM) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

摘要

巨噬细胞因其对细胞凋亡和 HIV 细胞病变效应的抵抗而成为病毒储存库。我们之前已经表明，凋亡抑制蛋白 (IAP) 赋予了正常巨噬细胞对 HIV-Vpr 诱导的细胞凋亡的抗性。在此，我们表明，第二线粒体激活的半胱天冬酶 (SMAC) 模拟物 (SM) 可诱导体外感染热稳定抗原表达的 R5 嗜性实验室株、慢性感染 U1 细胞以及从 HIV 感染者体内获得的单核细胞衍生巨噬细胞 (MDM) 的凋亡。为了了解控制 SM 诱导细胞死亡的机制，我们表明，SM 诱导的原发性 HIV 感染巨噬细胞的细胞死亡不依赖于巨噬细胞感染 HIV 后获得 M1 表型。相反，SM 诱导的细胞死亡被发现是由 IAP 介导的，因为 siRNA 下调 IAP 诱导了 HIV 感染的巨噬细胞的细胞死亡。此外，HIV 感染导致受体相互作用蛋白激酶-1 (RIPK1) 降解，而 SM 处理后与 IAP1/2 下调一起，可能导致巨噬细胞凋亡。总之，我们的结果表明，SM 选择性地诱导体外感染 HIV 的原代人巨噬细胞凋亡，可能通过 RIPK1 实现。此外，IAP 途径的调节可能是体内选择性杀伤 HIV 感染的巨噬细胞的潜在策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/7c43aa5468b2/41598_2021_2146_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/ed3d3b2bbd04/41598_2021_2146_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/c5575aad7546/41598_2021_2146_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/ed034fdc4437/41598_2021_2146_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/0468bbfbc369/41598_2021_2146_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/57ad3ecc5ad5/41598_2021_2146_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/7b4aa3874006/41598_2021_2146_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/8acaf545a752/41598_2021_2146_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/7c43aa5468b2/41598_2021_2146_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/ed3d3b2bbd04/41598_2021_2146_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/c5575aad7546/41598_2021_2146_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/ed034fdc4437/41598_2021_2146_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/0468bbfbc369/41598_2021_2146_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/57ad3ecc5ad5/41598_2021_2146_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/7b4aa3874006/41598_2021_2146_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/8acaf545a752/41598_2021_2146_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/57c2/8617210/7c43aa5468b2/41598_2021_2146_Fig8_HTML.jpg

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