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Discovery of novel immunotherapeutic drug candidates for sciatic nerve injury using bioinformatic analysis and experimental verification

Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Li, Shengyou;
Affiliation
Department of Neurosurgery ,The Second Affiliated Hospital of Xi’an Jiao Tong University ,Xi’an ,China
Yu, Beibei;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Gao, Xue;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Zheng, Yi;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Ma, Teng;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Hao, Yiming;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Wu, Haining;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Wei, Bin;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Wei, Yitao;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Luo, Zhuojing;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Xia, Bing;
Affiliation
Department of Orthopedics ,Xijing Hospital ,Fourth Military Medical University ,Xi’an ,China
Huang, Jinghui

Inflammation following nerve injury and surgery often causes peripheral nerve adhesion (PNA) to the surrounding tissue. Numerous investigations independently examined the prevention or inhibition of PNA, however, an intervention targeting macrophages has not been fully elucidated. Basement membrane (BM) genes are known to modulate central nervous system (CNS) inflammation, however, their activities in the peripheral nervous system (PNS) remains undiscovered. In this report, we carried out weighted correlation network analysis (WCNA) to screen for principal sciatic nerve injury (SNI) module genes. Once an association between the module and BM genes was established, the protein–protein interaction (PPI) and immune infiltration analyses were employed to screen for relevant BM-related immune genes (Itgam, SDC1, Egflam, and CD44) in SNI. Subsequently, using the Drug SIGnatures (DSigDB) database and molecular docking, we demonstrated that Trichostatin A (TSA) interacted with key immune genes. TSA is known to enhance M2 macrophage expression and attenuate fibrosis. Nevertheless, the significance of the epigenetic modulation of macrophage phenotypes in dorsal root ganglion (DRG) is undetermined after SNI. In this article, we examined the TSA role in fibrogenesis and macrophage plasticity associated with DRG. We revealed that TSA enhanced M2 macrophage aggregation, inhibited fibroblast activation, and improved sciatic nerve regeneration (SNR) and sensory functional recovery (FR) after SNI. In addition, TSA suppressed M1 macrophages and enhanced M2 macrophage invasion within the DRG tissue. Furthermore, TSA dramatically reduced IL-1β and TNFα levels, while upregulating IL-10 level. In summary, this research revealed for the first time that TSA alleviates fibrosis in DRG by promoting an M1 to M2 macrophage transition, which, in turn, accelerates SNR.

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License Holder: Copyright © 2022 Li, Yu, Gao, Zheng, Ma, Hao, Wu, Wei, Wei, Luo, Xia and Huang.

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