Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway

Ma, Hongdao; Wang, Chenfeng; Han, Lin; Kong, Fanqi; Liu, Zhixiao; Zhang, Bangke; Chu, Wenxiang; Wang, Haibin; Wang, Liang; Li, Qisheng; Peng, Weilin; Yang, Haisong; Han, Chaofeng; Lu, Xuhua

doi:10.7150/ijbs.84564

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Int J Biol Sci 2023; 19(15):4865-4882. doi:10.7150/ijbs.84564 This issue Cite

Research Paper

Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway

Hongdao Ma^1†, Chenfeng Wang^1†, Lin Han^2†, Fanqi Kong¹, Zhixiao Liu³, Bangke Zhang¹, Wenxiang Chu¹, Haibin Wang¹, Liang Wang¹, Qisheng Li¹, Weilin Peng¹, Haisong Yang¹, Chaofeng Han^3✉, Xuhua Lu^1✉

1. Department of Orthopaedics, Shanghai Changzheng Hospital, Shanghai 200003, China.
2. Department of Orthopaedics, Third Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
3. Department of Histology and Embryology, Naval Medical University, Shanghai 200433, China.
†These authors contributed equally to this study

Citation:

Ma H, Wang C, Han L, Kong F, Liu Z, Zhang B, Chu W, Wang H, Wang L, Li Q, Peng W, Yang H, Han C, Lu X. Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway. Int J Biol Sci 2023; 19(15):4865-4882. doi:10.7150/ijbs.84564. https://www.ijbs.com/v19p4865.htm

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Abstract

Background: The JAK/STAT signaling pathway is the main inflammatory signal transduction pathway, whether JAK/STAT contributes the pathology of SCI and targeting the pathway will alleviate SCI needs to be addressed. Here, we explored the therapeutic effect of pan-JAK inhibitor tofacitinib (TOF) on secondary injury after SCI and explained the underlying mechanisms.

Methods: SCI model in rat was established to evaluate the therapeutic effects of TOF treatment in vivo. Histological and behavioral analyses were performed at different time points after SCI. In vitro, the effects of TOF on pro-inflammatory activation of primary microglia and BV2 cells were analyzed by western blot analysis, fluorescent staining, qPCR and flow cytometry. The neuroprotection of TOF was detected using a co-culture system with primary neurons and microglia.

Results: TOF can effectively improve motor dysfunction caused by spinal cord injury in rats. TOF administration in the early stage of inflammation can effectively inhibit neuronal apoptosis and scar tissue formation, and promote the repair of axons and nerve fibers. Further studies have demonstrated that TOF suppresses inflammation caused by spinal cord injury by inhibiting the activation of microglia to pro-inflammatory phenotype in vivo and in vitro. Additionally, an interesting phenomenon is revealed in our results that TOF exhibits superior neuronal protection during inflammation in vitro.

Conclusions: Our study showed that TOF could regulate microglial activation via JAK / STAT pathway and promote the recovery of motor function after SCI, which is of great significance for the immunotherapy of SCI.

Keywords: spinal cord injury, tofacitinib, microglia, neuron, JAK/STAT pathway

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APA

Ma, H., Wang, C., Han, L., Kong, F., Liu, Z., Zhang, B., Chu, W., Wang, H., Wang, L., Li, Q., Peng, W., Yang, H., Han, C., Lu, X. (2023). Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway. International Journal of Biological Sciences, 19(15), 4865-4882. https://doi.org/10.7150/ijbs.84564.

ACS

Ma, H.; Wang, C.; Han, L.; Kong, F.; Liu, Z.; Zhang, B.; Chu, W.; Wang, H.; Wang, L.; Li, Q.; Peng, W.; Yang, H.; Han, C.; Lu, X. Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway. Int. J. Biol. Sci. 2023, 19 (15), 4865-4882. DOI: 10.7150/ijbs.84564.

NLM

CSE

Ma H, Wang C, Han L, Kong F, Liu Z, Zhang B, Chu W, Wang H, Wang L, Li Q, Peng W, Yang H, Han C, Lu X. 2023. Tofacitinib Promotes Functional Recovery after Spinal Cord Injury by Regulating Microglial Polarization via JAK/STAT Signaling Pathway. Int J Biol Sci. 19(15):4865-4882.

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