Monocytes promote acute neuroinflammation and become pathological microglia in neonatal hypoxic-ischemic brain injury.
Monocytes promote acute neuroinflammation and become pathological microglia in neonatal hypoxic-ischemic brain injury.
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作者：
Chen HR;Chen CW;Kuo YM;Chen B;Kuan IS;Huang H;Lee J;Anthony N;Kuan CY;Sun YY
原理：单核细胞属于单核吞噬细胞系统，是组织损伤和感染的免疫应答者。也有单核细胞转化为小胶质细胞样细胞的报告。本研究旨在探讨单核细胞在小胶质细胞个体发育中的作用以及新生小鼠缺氧缺血性脑损伤的发病机制。研究方法：我们使用了三种遗传学方法来跟踪单核细胞的发育，包括CX 3CR 1GFP/+; CCR 2 RFP/+报告小鼠，GFP+单核细胞的过继转移，以及CCR 2-CreER小鼠的命运作图，在有或没有脂多糖（LPS，0.3 mg/kg）致敏的Vannucci HI的新生小鼠脑中。我们还使用遗传学（CCR 2 RFP/ RFP，CCR 2敲除）和药理学方法（RS 102895，CCR 2拮抗剂）来测试单核细胞内流在LPS/HI脑损伤中的作用。结果：CCR 2+单核细胞经脉络丛进入胚胎晚期脑，但迅速转化为CX 3CR 1+阿米巴样小胶质细胞（AMCs）。出生后CCR 2+单核细胞的流入减少，但在HI或LPS致敏HI（LPS/HI）脑损伤后复发，特别是在海马。CCR 2-CreER命运作图显示，LPS/HI后4 d内CCR 2+单核细胞转化为CD 68 + TNFα+巨噬细胞，并在损伤后至少5个月内维持TNFα+ MHCII+巨噬细胞或Tmem 119 + Sall 1 + P2 RY 12+分支小胶质细胞的形态。趋化因子受体CCR 2的基因缺失显著减少了单核细胞的流入，促炎和抗炎细胞因子的表达，以及脑损伤。LPS/HI后应用RS 102895还可减少炎症反应和脑损伤，从而改善认知功能。结论：这些结果表明，单核细胞促进急性炎症反应，并可能成为新生儿LPS/HI损伤后很长时间的病理性小胶质细胞。此外，阻断单核细胞的流入可能是新生儿脑损伤的潜在治疗方法。
Rationale: Monocytes belong to the mononuclear phagocyte system and are immune responders to tissue injury and infection. There were also reports of monocytes transforming to microglia-like cells. Here we explore the roles of monocytes in microglia ontogeny and the pathogenesis of neonatal cerebral hypoxic-ischemic (HI) brain injury in mice. Methods: We used three genetic methods to track the development of monocytes, including CX3CR1GFP/+; CCR2RFP/+ reporter mice, adoptive transfer of GFP+ monocytes, and fate-mapping with CCR2-CreER mice, in neonatal mouse brains with or without lipopolysaccharide (LPS, 0.3 mg/kg)-sensitized Vannucci HI. We also used genetic (CCR2RFP/ RFP, CCR2 knockout) and pharmacological methods (RS102895, a CCR2 antagonist) to test the roles of monocytic influx in LPS/HI brain injury. Results: CCR2+ monocytes entered the late-embryonic brains via choroid plexus, but rapidly became CX3CR1+ amoeboid microglial cells (AMCs). The influx of CCR2+ monocytes declined after birth, but recurred after HI or LPS-sensitized HI (LPS/HI) brain injury, particularly in the hippocampus. The CCR2-CreER-based fate-mapping showed that CCR2+ monocytes became CD68+ TNFα+ macrophages within 4 d after LPS/HI, and maintained as TNFα+ MHCII+ macrophages or persisted as Tmem119+ Sall1+ P2RY12+ ramified microglia for at least five months after injury. Genetic deletion of the chemokine receptor CCR2 markedly diminished monocytic influx, the expression of pro- and anti-inflammatory cytokines, and brain damage. Post-LPS/HI application of RS102895 also reduced inflammatory responses and brain damage, leading to better cognitive functions. Conclusion: These results suggest that monocytes promote acute inflammatory responses and may become pathological microglia long after the neonatal LPS/HI insult. Further, blocking the influx of monocytes may be a potential therapy for neonatal brain injury.