Fang Xue, Jia Haiying, Pan Shaoshan, Liu Qian, Wang Qian, Feng Ye, Ding Weiping, Luo Tianzhi
CAS Key Laboratory of Mechanical Behavior and Design of Materials, Department of Modern Mechanics, University of Science and Technology of China, Hefei, China.
Chinese People's Liberation Army Strategic Support Force Special Medical Center, Beijing, China.
Cell Biochem Funct. 2025 Mar;43(3):e70061. doi: 10.1002/cbf.70061.
Microglia, as resident immune cells in the brain, adhere to the extracellular matrix and typically exhibit anti-inflammatory polarization under normal physiological conditions. Despite their pivotal roles, the regulatory effects of extracellular matrix properties on microglial function and the associated molecular mechanisms remain inadequately understood. Here, we elucidate how matrix stiffness modulates interleukin-10 (IL-10) secretion in human microglia (HMC3) via yes-associated protein (YAP)-mediated mechanotransduction. Using soft collagen Ⅰ-coated hydrogels, we observed a substantial reduction in IL-10 secretion, accompanied by a decrease in the expression and nuclear localization of YAP compared to cells adhered to glass substrates. With increasing hydrogel substrate stiffness, the expression and nuclear localization of YAP were enhanced, leading to an elevated secretion of IL-10. Subsequently, to further investigate the relationship between YAP and IL-10, we performed YAP depletion experiments, which revealed that nuclear exclusion of YAP suppressed IL-10 secretion. Interestingly, overexpression of YAP in microglia did not markedly affect IL-10 levels. We seeded YAP-knockdown microglia onto hydrogels of varying stiffness, and no significant differences were observed in IL-10 secretion. Our findings suggested that cytoskeletal polymerization was crucial for the regulation of IL-10 secretion mediated by YAP. Given the crucial role of IL-10 in the tumor microenvironment, we further found shYAP-microglia attenuated the pro-proliferative effect of microglia on gliomas. Besides, when YAP was silenced, actin of human microglia decreased, and their contractility was weakened. In summary, this study identifies YAP as a pivotal molecule in controlling cytokine secretion and sensing matrix stiffness in microglia. These insights offer potential therapeutic avenues for glioma treatment by targeting YAP-mediated pathways in microglial cells.
小胶质细胞作为大脑中的常驻免疫细胞，附着于细胞外基质，在正常生理条件下通常表现出抗炎极化。尽管它们起着关键作用，但细胞外基质特性对小胶质细胞功能的调节作用及其相关分子机制仍未得到充分了解。在这里，我们阐明了基质硬度如何通过Yes相关蛋白（YAP）介导的机械转导调节人小胶质细胞（HMC3）中白细胞介素-10（IL-10）的分泌。使用软胶原Ⅰ包被的水凝胶，我们观察到与附着在玻璃基质上的细胞相比，IL-10分泌显著减少，同时YAP的表达和核定位也降低。随着水凝胶底物硬度的增加，YAP的表达和核定位增强，导致IL-10分泌增加。随后，为了进一步研究YAP与IL-10之间的关系，我们进行了YAP缺失实验，结果表明YAP的核排除抑制了IL-10的分泌。有趣的是，小胶质细胞中YAP的过表达并未显著影响IL-10水平。我们将YAP敲低的小胶质细胞接种到不同硬度的水凝胶上，IL-10分泌未观察到显著差异。我们的研究结果表明，细胞骨架聚合对于YAP介导的IL-10分泌调节至关重要。鉴于IL-10在肿瘤微环境中的关键作用，我们进一步发现shYAP-小胶质细胞减弱了小胶质细胞对胶质瘤的促增殖作用。此外，当YAP沉默时，人小胶质细胞的肌动蛋白减少，其收缩性减弱。总之，本研究确定YAP是控制小胶质细胞中细胞因子分泌和感知基质硬度的关键分子。这些见解为通过靶向小胶质细胞中YAP介导的途径治疗胶质瘤提供了潜在的治疗途径。
