Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
Alzheimer's Therapeutic Research Institute, Keck School of Medicine, University of Southern California, 9880 Mesa Rim Road, San Diego, CA 92121, USA.
Viruses. 2024 Sep 24;16(10):1509. doi: 10.3390/v16101509.
Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2 mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH ( = 42) and people without HIV (PWoH; = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2 mice, with increased IBA1 protein in TREM2 hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.
髓样细胞触发受体 2（TREM2）参与神经炎症和与 HIV 相关的神经认知障碍（NCI）。使用大麻的 HIV 感染者（PWH）表现出较低的炎症和神经紊乱。我们假设 TREM2 功能障碍介导 HIV 神经发病机制，并且可以被大麻素逆转。我们使用 EcoHIV 感染的野生型（WT）和 TREM2 突变小鼠来研究 HIV 对 TREM2 和行为的影响。通过 RNA 测序和 qPCR，研究了来自 PWH（=42）和无 HIV（PWoH；=19）的单核细胞衍生的巨噬细胞（MDMs）中 TREM2 和相关基因的表达，这些人有不同程度的大麻使用情况。通过免疫细胞化学（ICC）和 ELISA 评估膜结合和可溶性 TREM2（sTREM2）的差异。EcoHIV 在 WT 小鼠中增加了不成熟和 C 末端片段形式的 TREM2，但在 TREM2 小鼠中没有增加，TREM2 海马中的 IBA1 蛋白增加，与记忆测试表现更差相关。TREM2 mRNA 水平在 PWoH 中随年龄增长而增加，但在 PWH 中没有增加。大麻二酚（CBD）治疗单独增加 TREM2 mRNA，同时增加 IL1β。RNA-seq 显示，与天真对照相比，使用大麻的 PWH 中 TREM2 相关转录物上调。IL1β 增加了 sTREM2 并减少了膜结合的 TREM2，CBD 部分逆转了这些效应。这些发现表明 HIV 影响大麻和 CBD 调节的 TREM2 表达，为治疗策略提供了见解。
