Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism
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...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824005139 |
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| author | Hong Gong Yao Lu Shi-Long Deng Ke-Yi Lv Jing Luo Yi Luo Zhu-Lin Du Ling-Feng Wu Tian-Yao Liu Xia-Qing Wang Jing-Hui Zhao Lian Wang Mei-Ling Xia Dong-Mei Zhu Li-Wei Wang Xiao-Tang Fan |
| author_facet | Hong Gong Yao Lu Shi-Long Deng Ke-Yi Lv Jing Luo Yi Luo Zhu-Lin Du Ling-Feng Wu Tian-Yao Liu Xia-Qing Wang Jing-Hui Zhao Lian Wang Mei-Ling Xia Dong-Mei Zhu Li-Wei Wang Xiao-Tang Fan |
| author_sort | Hong Gong |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4f2c043238ae4d13a8faeec0d97eb6f4 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-4f2c043238ae4d13a8faeec0d97eb6f42025-01-09T06:13:07ZengElsevierPharmacological Research1096-11862025-01-01211107568Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autismHong Gong0Yao Lu1Shi-Long Deng2Ke-Yi Lv3Jing Luo4Yi Luo5Zhu-Lin Du6Ling-Feng Wu7Tian-Yao Liu8Xia-Qing Wang9Jing-Hui Zhao10Lian Wang11Mei-Ling Xia12Dong-Mei Zhu13Li-Wei Wang14Xiao-Tang Fan15Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment 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, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, China; Nursing Department, The Affiliated Hospital of Southwest Medical University, Sichuan Province, Luzhou 646000, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, China; Battalion 7 of the Cadet Brigade, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, ChinaDepartment of Hospital Infection Control, Chongqing Health Center for Women and Children, Chongqing 401147, China; Department of Hospital Infection Control, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, ChinaDepartment of Anesthesiology, Xuzhou Central Hospital, Xuzhou 221009, China; Department of Anesthesiology, Xuzhou Clinical College of Xuzhou Medical University, Xuzhou 221009, China; Corresponding author at: Department of Anesthesiology, Xuzhou Central Hospital, Xuzhou 221009, China.Department of Military Cognitive Psychology, School of Psychology, Third Military Medical University (Army Medical University), Chongqing 40038, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S1043661824005139ASDMrp14NeuroinflammationMicrogliaMyelination deficit |
| spellingShingle | Hong Gong Yao Lu Shi-Long Deng Ke-Yi Lv Jing Luo Yi Luo Zhu-Lin Du Ling-Feng Wu Tian-Yao Liu Xia-Qing Wang Jing-Hui Zhao Lian Wang Mei-Ling Xia Dong-Mei Zhu Li-Wei Wang Xiao-Tang Fan Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism Pharmacological Research ASD Mrp14 Neuroinflammation Microglia Myelination deficit |
| title | Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| title_full | Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| title_fullStr | Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| title_full_unstemmed | Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| title_short | Targeting S100A9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| title_sort | targeting s100a9 attenuates social dysfunction by modulating neuroinflammation and myelination in a mouse model of autism |
| topic | ASD Mrp14 Neuroinflammation Microglia Myelination deficit |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824005139 |
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