TREM-1 Protects HIV-1-Infected Macrophages from Apoptosis through Maintenance of Mitochondrial Function
TREM-1 Protects HIV-1-Infected Macrophages from Apoptosis through Maintenance of Mitochondrial Function
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DOI：
10.1128/mbio.02638-19
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Spector, Stephen A.
中科院分区：
文献类型：
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作者：
Campbell, Grant R.;To, Rachel K.;Spector, Stephen A.
巨噬细胞是潜伏的人类免疫缺陷1型(HIV)感染的蓄水池，也是根除HIV的障碍。与CD4(+)T细胞相比，巨噬细胞对急性HIV感染的细胞病变具有抵抗力。新的数据表明，TREM1(触发髓系细胞上表达的受体1)在这种对HIV介导的细胞病变的抵抗中发挥了作用。在这里，我们发现，在HIV感染后，巨噬细胞增加了BCL2、BCLXL、TREM1、Mfn1和Mfn2的表达，并增加了BCL2L11(BIM)的转位，降低了BCL2相关的细胞死亡激动剂(BAD)和Bax的表达，同时在28天内保持了95%的存活率。HIV蛋白TAT和gp120以及来自HIV长末端重复区域的富含Gu的单链RNA(SsRNA)(RNA40)(以及天然的Toll样受体8[TLR8]激动剂)可以产生类似的效果。在HIV感染的巨噬细胞中沉默TREM1导致BCL2、BCLXL、Mfn1和Mfn2的表达降低，BAD和Bax的表达增加。这与线粒体膜电位(Delta Psi M)的破坏导致细胞色素c和caspase 9裂解的释放而导致的细胞凋亡显著增加有关。将TREM1沉默的巨噬细胞暴露于TAT、gp120或RNA40后，同样会导致Delta psim的破坏、细胞色素c的释放、caspase9的裂解和细胞凋亡。因此，我们的发现确定了一种机制，HIV通过依赖TREM1上调BCL2家族蛋白和丝裂原蛋白来抑制BCL2L11介导的Delta psim的破坏和随后的凋亡，从而促进巨噬细胞的存活。这些发现表明，TREM1可以成为消除巨噬细胞中艾滋病毒储存库的有用靶点。重要的是，人类免疫缺陷病毒(HIV)治疗面临的主要挑战是制定消除病毒的策略。实现这一目标的一个障碍是缺乏一种能够安全地从包括巨噬细胞在内的所有静止/潜伏的宿主中消除艾滋病毒的方法。巨噬细胞是先天免疫系统的关键部分，负责识别入侵的微生物并向其他免疫细胞发送适当的信号。在这里，我们发现HIV诱导蛋白TREM1(在髓系细胞上表达的触发受体1)上调，这是抗凋亡蛋白表达增加的信号，从而促进了HIV感染的巨噬细胞的存活。
Macrophages are a reservoir for latent human immunodeficiency type 1 (HIV) infection and a barrier to HIV eradication. In contrast to CD4(+) T cells, macrophages are resistant to the cytopathic effects of acute HIV infection. Emerging data suggest a role for TREM1 (triggering receptor expressed on myeloid cells 1) in this resistance to HIV-mediated cytopathogenesis. Here, we show that upon HIV infection, macrophages increase the expression of BCL2, BCLXL, TREM1, mitofusin 1 (MFN1), and MFN2 and the translocation of BCL2L11 (BIM) to the mitochondria and decrease the expression of BCL2-associated agonist of cell death (BAD) and BAX while maintaining a 95% survival rate over 28 days. The HIV proteins Tat and gp120 and the GU-rich single-stranded RNA (ssRNA) (RNA40) from the HIV long terminal repeat region (and a natural Toll-like receptor 8 [TLR8] agonist) induced similar effects. TREM1 silencing in HIV-infected macrophages led to decreased expression of BCL2, BCLXL, MFN1, and MFN2 and increased expression of BAD and BAX. This correlated with a significant increase in apoptosis mediated by a disruption of the mitochondrial membrane potential (Delta psi m), leading to the release of cytochrome c and caspase 9 cleavage. Exposure of TREM1-silenced macrophages to Tat, gp120, or RNA40 similarly resulted in the disruption of Delta psi m, cytochrome c release, caspase 9 cleavage, and apoptosis. Thus, our findings identify a mechanism whereby HIV promotes macrophage survival through TREM1-dependent upregulation of BCL2 family proteins and mitofusins that inhibits BCL2L11-mediated disruption of Delta psi m and subsequent apoptosis. These findings indicate that TREM1 can be a useful target for elimination of the HIV reservoir in macrophages.IMPORTANCE The major challenge to human immunodeficiency virus (HIV) treatment is the development of strategies that lead to viral eradication. A roadblock to accomplishing this goal is the lack of an approach that would safely eliminate HIV from all resting/latent reservoirs, including macrophages. Macrophages are a key part of the innate immune system and are responsible for recognizing invading microbes and sending appropriate signals to other immune cells. Here, we found that HIV induces the upregulation of the protein TREM1 (triggering receptor expressed on myeloid cells 1), which signals an increase in the expression of antiapoptotic proteins, thus promoting survival of HIV-infected macrophages.