Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Zhifeng Huang; Zijing Ding; Yangting Xu; Caiyun Xi; Liqiong He; Hui Luo; Qulian Guo; Changsheng Huang

doi:10.3389/fphar.2023.1069331

Downregulation of nuclear STAT2 protein in the spinal dorsal horn is involved in neuropathic pain following chronic constriction injury of the rat sciatic nerve

Front Pharmacol. 2023 Jan 18:14:1069331. doi: 10.3389/fphar.2023.1069331. eCollection 2023.

Authors

Zhifeng Huang¹, Zijing Ding¹, Yangting Xu², Caiyun Xi¹, Liqiong He¹, Hui Luo^{1

3}, Qulian Guo^{1

3}, Changsheng Huang^{1

3}

Affiliations

¹ Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China.
² Xiangya School of Medicine, Central South University, Changsha, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.

Abstract

Regulation of gene transcription in the spinal dorsal horn (SDH) plays a critical role in the pathophysiology of neuropathic pain. In this study, we investigated whether the transcription factor STAT2 affects neuropathic pain and evaluated its possible mechanisms. A proteomic analysis showed that the nuclear fraction of STAT2 protein in the SDH was downregulated after chronic constriction injury of the rat sciatic nerve, which was associated with the development of neuropathic pain. Similarly, siRNA-induced downregulation of STAT2 in the SDH of naïve rats also resulted in pain hypersensitivity. Using RNA-sequencing analysis, we showed that reduction of nuclear STAT2 after chronic constriction injury was associated with increased expression of microglial activation markers, including the class II transactivator and major histocompatibility complex class II proteins. In addition, siRNA-induced downregulation of STAT2 promoted microglial activation and pro-inflammatory cytokine expression in the SDH. Taken together, these results showed that chronic constriction injury caused downregulation of nuclear STAT2 in the SDH, which may result in microglial activation and development of neuropathic pain. Our findings indicate that restoration of nuclear expression of STAT2 could be a potential pathway for the treatment of neuropathic pain.

Keywords: STAT2; microglia; neuropathic pain; proteomics; spinal dorsal horn.

Grants and funding

This research was funded by the National Natural Science Foundation of China (82071249, 81771207 and 82000388), and Natural Science Foundation of Hunan Province (2020JJ4900).