Photo-enhancement of macrophage phagocytic activity via Rac1-mediated signaling pathway: Implications for bacterial infection

Phagocytosis and the subsequent destruction of invading pathogens by macrophages are indispensable steps in host immune responses to microbial infections. Low-power laser irradiation (LPLI) has been found to exert photobiological effects on immune responses, but the signaling mechanisms underlying this photobiomodulation of phagocytosis remains largely unknown. Here, we demonstrated for the first time that LPLI enhanced the phagocytic activity of macrophages by stimulating the activation of Rac1. The overexpression of constitutively activated Rac1 clearly enhanced LPLI-induced phagocytosis, whereas the overexpression of dominant negative Rac1 exerted the opposite effect. The phosphorylation of cofilin was involved in the effects of LPLI on phagocytosis, which was regulated by the membrane translocation and activation of Rac1. Furthermore, the photoactivation of Rac1 was dependent on the Src/PI3K/Vav1 pathway. The inhibition of the Src/PI3K pathway significantly suppressed LPLI-induced actin polymerization and phagocytosis enhancement. Additionally, LPLI-treated mice exhibited increased survival and a decreased organ bacterial load when challenged with Listeria monocytogenes, indicating that LPLI enhanced macrophage phagocytosis in vivo. These findings highlight the important roles of the Src/PI3K/Vav1/Rac1/cofilin pathway in regulating macrophage phagocytosis and provide a potential strategy for treating phagocytic deficiency via LPLI. (C) 2016 Published by Elsevier Ltd.

巨噬细胞的吞噬作用以及随后对入侵病原体的破坏是宿主对微生物感染的免疫反应中不可或缺的步骤。低功率激光照射（LPLI）已被发现对免疫反应具有光生物学效应，但这种对吞噬作用的光生物调节的信号机制在很大程度上仍然未知。在此，我们首次证明LPLI通过刺激Rac1的激活增强了巨噬细胞的吞噬活性。组成型激活的Rac1的过表达明显增强了LPLI诱导的吞噬作用，而显性负性Rac1的过表达则产生相反的效果。丝切蛋白的磷酸化参与了LPLI对吞噬作用的影响，这是由Rac1的膜转位和激活所调节的。此外，Rac1的光激活依赖于Src/PI3K/Vav1通路。对Src/PI3K通路的抑制显著抑制了LPLI诱导的肌动蛋白聚合和吞噬作用增强。另外，当用单核细胞增生李斯特菌攻击时，LPLI处理的小鼠表现出更高的存活率和更低的器官细菌负荷，这表明LPLI在体内增强了巨噬细胞的吞噬作用。这些发现强调了Src/PI3K/Vav1/Rac1/丝切蛋白通路在调节巨噬细胞吞噬作用中的重要作用，并为通过LPLI治疗吞噬缺陷提供了一种潜在策略。（C）2016由爱思唯尔有限公司出版