Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration into the brain disrupting daytime locomotion.
Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration into the brain disrupting daytime locomotion.
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DOI：
10.1038/s42003-022-03410-z
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发表时间：
2022-05-16
影响因子：
5.9
通讯作者：
Shiau, Celia E.
中科院分区：
文献类型：
--
作者：
Kwon, Victoria;Cai, Peiwen;Dixon, Cameron T.;Hamlin, Victoria;Spencer, Caroline G.;Rojas, Alison M.;Shiau, Celia E.
众所周知，炎症会扰乱正常行为，但潜在的神经免疫相互作用仍然难以捉摸。在这里，我们使用一组针对特定巨噬细胞功能障碍和小胶质细胞缺陷而选择的斑马鱼突变体，研究了不适当的巨噬细胞诱发的炎症是否改变了中枢神经系统对日常生活中动物运动的控制。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，但优先在白天游泳较少，这可能表明动机较低，而不是身体损伤。检查它们的大脑活动和结构表明，中性粒细胞异常渗透的多巴胺能下行回路受损。此外，中性粒细胞的耗尽恢复了白天的活动。恢复野生型巨噬细胞逆转了行为和中性粒细胞的异常，而其他三个缺乏小胶质细胞的突变体未能复制nlrc3l突变体。总体而言，我们揭示了在没有小胶质细胞的情况下，具有升高的促炎信号的外周炎性巨噬细胞(包括IL1β、肿瘤坏死因子α、cxcl8a)是如何选择中性粒细胞渗入大脑的，从而潜在地使局部电路调制影响白天的运动。外周炎性巨噬细胞被发现通过将中性粒细胞招募到大脑中来调节斑马鱼的白天活动。
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. Peripheral inflammatory macrophages are found to modulate daytime locomotion of zebrafish via recruiting neutrophils into the brain.
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