Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Commun Biol. 2022 May 16;5(1):464. doi: 10.1038/s42003-022-03410-z.
Inflammation is known to disrupt normal behavior, yet the underlying neuroimmune interactions remain elusive. Here, we investigated whether inappropriate macrophage-evoked inflammation alters CNS control of daily-life animal locomotion using a set of zebrafish mutants selected for specific macrophage dysfunction and microglia deficiency. Large-scale genetic and computational analyses revealed that NOD-like receptor nlrc3l mutants are capable of normal motility and visuomotor response, but preferentially swim less in the daytime, suggesting possible low motivation rather than physical impairment. Examining their brain activities and structures implicates impaired dopaminergic descending circuits, where neutrophils abnormally infiltrate. Furthermore, neutrophil depletion recovered daytime locomotion. Restoring wild-type macrophages reversed behavioral and neutrophil aberrations, while three other microglia-lacking mutants failed to phenocopy nlrc3l mutants. Overall, we reveal how peripheral inflammatory macrophages with elevated pro-inflammatory cues (including il1β, tnfα, cxcl8a) in the absence of microglia co-opt neutrophils to infiltrate the brain, thereby potentially enabling local circuitry modulation affecting daytime locomotion.
炎症已知会扰乱正常行为，但潜在的神经免疫相互作用仍然难以捉摸。在这里，我们研究了特定巨噬细胞功能障碍和小胶质细胞缺失的一组斑马鱼突变体，是否会导致不合适的巨噬细胞引发的炎症改变中枢神经系统对日常动物运动的控制。大规模的遗传和计算分析表明，NOD 样受体 nlrc3l 突变体能够正常运动和视觉运动反应，但白天更喜欢游泳少，这可能表明动机不足而不是身体受损。检查它们的大脑活动和结构表明多巴胺能下行回路受损，中性粒细胞异常浸润。此外，中性粒细胞耗竭恢复了白天的运动。恢复野生型巨噬细胞可逆转行为和中性粒细胞异常，而另外三种缺乏小胶质细胞的突变体则无法模拟 nlrc3l 突变体。总的来说，我们揭示了外周炎症性巨噬细胞在缺乏小胶质细胞的情况下，如何利用升高的促炎信号（包括 il1β、tnfα、cxcl8a）招募中性粒细胞浸润大脑，从而可能影响白天的运动。
