mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder
Autism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels...
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.818518/full |
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| author | Baojiang Wang Baojiang Wang Yueyuan Qin Qunyan Wu Xi Li Dongying Xie Zhongying Zhao Shan Duan |
| author_facet | Baojiang Wang Baojiang Wang Yueyuan Qin Qunyan Wu Xi Li Dongying Xie Zhongying Zhao Shan Duan |
| author_sort | Baojiang Wang |
| collection | DOAJ |
| description | Autism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels of the proinflammatory chemokine (C-C motif) ligand 5 (CCL5) in children with ASD, suggesting an aberrant inflammatory response appearing in the development of ASD. Mining of the expression data of brain or blood tissue from individuals with ASD reveals that mTOR signaling is aberrantly activated in ASD patients. Our in vitro study shows that suppression of mTOR reduces the gene expression and release of CCL5 from human microglia, supporting that CCL5 expression is regulated by mTOR activity. Furthermore, bacterial lipopolysaccharide (LPS)-induced CCL5 expression can be counteracted by siRNA against NF-κB, suggests a determining role of NF-κB in upregulating CCL5 expression. However, a direct regulatory relationship between the NF-κB element and the mTOR signaling pathway was not observed in rapamycin-treated cells. Our results show that the phosphorylated CREB can be induced to suppress CCL5 expression by outcompeting NF-κB in binding to CREB-binding protein (CREBBP) once the mTOR signaling pathway is inhibited. We propose that the activation of mTOR signaling in ASD may induce the suppression of phosphorylation of CREB, which in turn results in the increased binding of CREBBP to NF-κB, a competitor of phosphorylated CREB to drive expression of CCL5. Our study sheds new light on the inflammatory mechanisms of ASD and paves the way for the development of therapeutic strategy for ASD. |
| first_indexed | 2024-12-13T08:56:59Z |
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| id | doaj.art-ea53095f74184ffa933bc6d0ae6956d4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T08:56:59Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ea53095f74184ffa933bc6d0ae6956d42022-12-21T23:53:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-03-011310.3389/fimmu.2022.818518818518mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum DisorderBaojiang Wang0Baojiang Wang1Yueyuan Qin2Qunyan Wu3Xi Li4Dongying Xie5Zhongying Zhao6Shan Duan7Institute of Maternal and Child Medicine, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaLaboratory of Medical Genetics, Shenzhen Health Development Research and Data Management Center, Shenzhen, ChinaInstitute of Maternal and Child Medicine, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaInstitute of Maternal and Child Medicine, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaLaboratory of Medical Genetics, Shenzhen Health Development Research and Data Management Center, Shenzhen, ChinaDepartment of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, ChinaDepartment of Biology, Faculty of Science, Hong Kong Baptist University, Kowloon Tong, Hong Kong SAR, ChinaInstitute of Maternal and Child Medicine, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, ChinaAutism spectrum disorder (ASD) is a complex pervasive neurodevelopmental disorder and neuroinflammation may contribute to the pathogenesis of ASD. However, the exact mechanisms of abnormal release of proinflammatory mediators in ASD remain poorly understood. This study reports elevated plasma levels of the proinflammatory chemokine (C-C motif) ligand 5 (CCL5) in children with ASD, suggesting an aberrant inflammatory response appearing in the development of ASD. Mining of the expression data of brain or blood tissue from individuals with ASD reveals that mTOR signaling is aberrantly activated in ASD patients. Our in vitro study shows that suppression of mTOR reduces the gene expression and release of CCL5 from human microglia, supporting that CCL5 expression is regulated by mTOR activity. Furthermore, bacterial lipopolysaccharide (LPS)-induced CCL5 expression can be counteracted by siRNA against NF-κB, suggests a determining role of NF-κB in upregulating CCL5 expression. However, a direct regulatory relationship between the NF-κB element and the mTOR signaling pathway was not observed in rapamycin-treated cells. Our results show that the phosphorylated CREB can be induced to suppress CCL5 expression by outcompeting NF-κB in binding to CREB-binding protein (CREBBP) once the mTOR signaling pathway is inhibited. We propose that the activation of mTOR signaling in ASD may induce the suppression of phosphorylation of CREB, which in turn results in the increased binding of CREBBP to NF-κB, a competitor of phosphorylated CREB to drive expression of CCL5. Our study sheds new light on the inflammatory mechanisms of ASD and paves the way for the development of therapeutic strategy for ASD.https://www.frontiersin.org/articles/10.3389/fimmu.2022.818518/fullCCL5autism spectrum disorderNF-κBmTORproinflammatory cytokinesneurodevelopmental disorder |
| spellingShingle | Baojiang Wang Baojiang Wang Yueyuan Qin Qunyan Wu Xi Li Dongying Xie Zhongying Zhao Shan Duan mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder Frontiers in Immunology CCL5 autism spectrum disorder NF-κB mTOR proinflammatory cytokines neurodevelopmental disorder |
| title | mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder |
| title_full | mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder |
| title_fullStr | mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder |
| title_full_unstemmed | mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder |
| title_short | mTOR Signaling Pathway Regulates the Release of Proinflammatory Molecule CCL5 Implicated in the Pathogenesis of Autism Spectrum Disorder |
| title_sort | mtor signaling pathway regulates the release of proinflammatory molecule ccl5 implicated in the pathogenesis of autism spectrum disorder |
| topic | CCL5 autism spectrum disorder NF-κB mTOR proinflammatory cytokines neurodevelopmental disorder |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.818518/full |
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