Fan Changyuan, Huang Xinyi, Mei Jie, Shi Xuemeng, Zhang Hao, Liang Cong, Cui Shuzhi, Xing Yifan, Cao Biao, Liu Wei, Liu Huisheng, Liu Bo, Chang Wakam, Shao Mengle, Wei Gong-Hong, Liu Yan-Jun, Chen Zheng-Jun, Lin Zhaoyu, Xu Tao, Jiu Yaming
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 200031, Shanghai, China.
EMBO J. 2025 Jul 28. doi: 10.1038/s44318-025-00515-z.
Macrophages are critical innate immune cells that exhibit remarkable adaptability during pathogen infections. However, the relationship between their morphological plasticity and physiological functions remains largely elusive. Here, we discovered an unprecedented paradigm of macrophage adaptation within a few hours upon severe Gram-negative bacterial infections, characterized by the formation of dendrite-like pseudopods (DLPs). Using in vitro, microfluidic, and in vivo infection models, we demonstrate that these pseudopods enhance bacterial uptake by expanding the macrophage searching radius, thereby bolstering host defense. Mechanistically, Toll-like receptor 4 (TLR4) activation by Gram-negative bacterial lipopolysaccharide (LPS) upregulates the expression of macrophage-specific RhoGEF and ARHGEF3 in an NF-κB-dependent manner. ARHGEF3 localizes to dendrite-like pseudopods and enhances RhoA activity. Consequently, periodic cycles of actin assembly and disassembly propel the elongation of pseudopods, whereas vimentin intermediate filaments stabilize them. Importantly, infusion of DLP-equipped macrophages into Salmonella-infected mice reduced bacterial burden and infection severity. Together, our findings underscore how the dynamic response of macrophages to massive infections can augment immune defense against pathogenic bacteria.
巨噬细胞是关键的固有免疫细胞，在病原体感染期间表现出显著的适应性。然而，它们的形态可塑性与生理功能之间的关系在很大程度上仍不清楚。在此，我们发现了一种前所未有的巨噬细胞适应模式，即在严重革兰氏阴性细菌感染后的数小时内，其特征是形成树突状伪足（DLP）。利用体外、微流控和体内感染模型，我们证明这些伪足通过扩大巨噬细胞的搜索半径来增强细菌摄取，从而加强宿主防御。从机制上讲，革兰氏阴性细菌脂多糖（LPS）激活Toll样受体4（TLR4）以NF-κB依赖的方式上调巨噬细胞特异性RhoGEF和ARHGEF3的表达。ARHGEF3定位于树突状伪足并增强RhoA活性。因此，肌动蛋白组装和拆卸的周期性循环推动伪足伸长，而波形蛋白中间丝使其稳定。重要的是，将配备DLP的巨噬细胞注入感染沙门氏菌的小鼠体内可减轻细菌负荷和感染严重程度。总之，我们的研究结果强调了巨噬细胞对大规模感染的动态反应如何增强对病原菌的免疫防御。
