Gong Hong, Lu Yao, Deng Shi-Long, Lv Ke-Yi, Luo Jing, Luo Yi, Du Zhu-Lin, Wu Ling-Feng, Liu Tian-Yao, Wang Xia-Qing, Zhao Jing-Hui, Wang Lian, Xia Mei-Ling, Zhu Dong-Mei, Wang Li-Wei, Fan Xiao-Tang
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, China.
Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, China; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou 22100, China.
Pharmacol Res. 2025 Jan;211:107568. doi: 10.1016/j.phrs.2024.107568. Epub 2024 Dec 27.
Growing evidence supports a role for dysregulated neuroinflammation in autism. However, the underlying mechanisms of microglia-evoked neuroinflammation in the development of autistic phenotypes have not been elucidated. This study aimed to investigate the role and underlying mechanisms of microglial S100 calcium-binding protein A9 (S100A9) in autistic phenotypes. We utilized the BTBR T + tf/J (BTBR) mouse, a reliable preclinical model for autism that displays core behavioral features of autism as well as persistent immune dysregulation. A combination of behavioral, pharmacological, immunological, genetic, molecular, and transcriptomics approaches were used to uncover the potential role of S100A9 in autism. Significant overexpression of microglial S100A9 was observed in the hippocampus of BTBR mice. BTBR mice displayed decreased social communication and increased repetitive behaviors compared to C57BL/6 mice. Interestingly, the above social dysfunction was attenuated by a pharmacological inhibitor of S100A9, accompanied by a significant reduction in the activated microglia morphological phenotype, inflammatory receptors, and proinflammatory cytokines. Notably, S100A9 inhibition decreased c-Fos cells and promoted myelination in the cornu ammonis 3 of BTBR mice. Furthermore, the promyelinating compound administration ameliorated the autism-relevant behaviors in BTBR mice. Our findings indicate that microglia-derived S100A9 triggers the neuroinflammation cascade, myelination deficits, and social dysfunction. Targeting S100A9 could, therefore, be a promising therapeutic strategy for neuroinflammation-related neurodevelopmental disorders.
越来越多的证据支持神经炎症失调在自闭症中起作用。然而，小胶质细胞诱发的神经炎症在自闭症表型发展中的潜在机制尚未阐明。本研究旨在探讨小胶质细胞S100钙结合蛋白A9（S100A9）在自闭症表型中的作用及潜在机制。我们使用了BTBR T + tf/J（BTBR）小鼠，这是一种可靠的自闭症临床前模型，表现出自闭症的核心行为特征以及持续的免疫失调。采用行为学、药理学、免疫学、遗传学、分子生物学和转录组学方法相结合，以揭示S100A9在自闭症中的潜在作用。在BTBR小鼠的海马体中观察到小胶质细胞S100A9显著过表达。与C57BL/6小鼠相比，BTBR小鼠表现出社交沟通减少和重复行为增加。有趣的是，S100A9的药理学抑制剂减轻了上述社交功能障碍，同时活化的小胶质细胞形态表型、炎症受体和促炎细胞因子显著减少。值得注意的是，S100A9抑制减少了BTBR小鼠海马角3区的c-Fos细胞并促进了髓鞘形成。此外，给予促髓鞘形成化合物改善了BTBR小鼠的自闭症相关行为。我们的研究结果表明，小胶质细胞衍生的S100A9触发神经炎症级联反应、髓鞘形成缺陷和社交功能障碍。因此，靶向S100A9可能是治疗神经炎症相关神经发育障碍的一种有前景的治疗策略。
