Air pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation. WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2−/−, PHOX+/+, and PHOX−/−). Rats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2−/− mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation. Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.

中文翻译：

---

柴油机尾气损害 TREM2 以调节神经炎症

空气污染与神经退行性疾病有关，包括阿尔茨海默病 (AD)，而其潜在的神经免疫机制仍知之甚少。TREM2 是一种髓样细胞膜受体，是疾病相关小胶质细胞 (DAM) 细胞的关键调节因子，其中功能丧失的 TREM2 突变与 AD 风险增加有关。目前，TREM2在神经炎症中的基本功能是一个争议点。此外，空气污染对 TREM2 和 DAM 表型的影响在​​很大程度上是未知的。使用柴油机尾气 (DE) 作为城市空气污染暴露模型，我们试图解决其对 TREM2 表达、DAM 表型、小胶质细胞与神经血管系统的关联以及 TREM2 在 DE 诱导的神经炎症中的作用的影响。WYK 大鼠暴露于 DE（0、50、150、500 μg/m3) 吸入。在 28 天内向雄性小鼠（Trem2+/+、Trem2-/-、PHOX+/+ 和 PHOX-/-）气管内施用 DE 颗粒（DEP）一次（600 μg/小鼠）或 8 次（100 μg/小鼠） . 暴露于 DE 的大鼠在海马和额叶皮层中表现出倒 U 型的 Trem2 mRNA 表达模式，而 TREM2 蛋白整体减少，表明 TREM2 表达受损。额叶皮层和海马中 DAM 标记物 Cx3Cr1、Lyz2 和 Lpl 的分析也显示出倒 U 型表达模式，支持 DAM 表型的失调。此外，小胶质细胞-血管的结合以剂量依赖性方式随着 DE 吸入而降低。从机制上讲，气管内施用 DEP 仅在 Trem2+/+ 小鼠中增加了 Tnf (TNFα)、Ncf1 (p47PHOX) 和 Ncf2 (p67PHOX) mRNA 表达，其中 Il1b (IL-1β) 表达仅在 Trem2-/- 小鼠中升高，强调了 TREM2 在 DEP 诱导的神经炎症中的重要作用。总的来说，这些发现揭示了 TREM2 在空气污染如何调节神经炎症方面的新作用，并为将城市空气污染与 AD 联系起来的潜在机制提供了急需的见解。