Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte

Kai Chen; Xiaojin Wei; Wenjuan Zhang; Ruixuan Wang; Yaping Wang; Lin Yang

doi:10.1016/j.bbi.2024.05.007

Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte

Brain Behav Immun. 2024 May 10:119:836-850. doi: 10.1016/j.bbi.2024.05.007. Online ahead of print.

Authors

Kai Chen¹, Xiaojin Wei¹, Wenjuan Zhang², Ruixuan Wang³, Yaping Wang⁴, Lin Yang⁵

Affiliations

¹ Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, China; Department of Pain Management, the Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, Hunan Province, China; Clinical Research Center for Pain Medicine in Hunan Province, Changsha, Hunan Province, China.
² Department of the Laboratory, the Second Xiangya Hospital, Central South University, Changsha, China.
³ Bourns Engineering, The University of California, Riverside, CA 92521, USA.
⁴ Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, China; Department of Pain Management, the Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, Hunan Province, China; Clinical Research Center for Pain Medicine in Hunan Province, Changsha, Hunan Province, China. Electronic address: wangyaping6568@csu.edu.cn.
⁵ Department of Anesthesiology, the Second Xiangya Hospital, Central South University, Changsha, China; Department of Pain Management, the Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China; Hunan Province Center for Clinical Anesthesia and Anesthesiology, Research Institute of Central South University, Changsha, Hunan Province, China; Clinical Research Center for Pain Medicine in Hunan Province, Changsha, Hunan Province, China. Electronic address: linyang@csu.edu.cn.

PMID: 38735405
DOI: 10.1016/j.bbi.2024.05.007

Abstract

Introduction: During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN.

Methods: CSF samples were collected from both PHN patients and non-painful individuals (Control) to assess BMP4 and its antagonist Noggin levels. Besides, intrathecal administration of both CSF types was conducted in normal rats to evaluate the impact on pain behavior, glial activity, and inflammation.; Additionally, both Noggin and STAT3 antagonist-Stattic were employed to treat the PHN-CSF or exogenous BMP4 challenged cultured astrocytes to explore downstream signals. Finally, microglial depletion was performed prior to the PHN-CSF intervention so as to elucidate the microglia-astrocyte crosstalk.

Results: BMP4 levels were significantly higher in PHN-CSF compared to Control-CSF (P < 0.001), with a positive correlation with pain duration (P < 0.05, r = 0.502). Comparing with the Control-CSF producing moderate paw withdrawal threshold (PWT) decline and microglial activation, PHN-CSF further exacerbated allodynia and triggered both microglial and astrocytic activation (P < 0.05). Moreover, PHN-CSF rather than Control-CSF evoked microglial proliferation and pro-inflammatory transformation, reinforced iron storage, and activated astrocytes possibly through both SMAD159 and STAT3 signaling, which were all mitigated by the Noggin application (P < 0.05). Next, both Noggin and Stattic effectively attenuated BMP4-induced GFAP and IL-6 upregulation, as well as SMAD159 and STAT3 phosphorylation in the cultured astrocytes (P < 0.05). Finally, microglial depletion diminished PHN-CSF induced astrogliosis, inflammation and endogenous BMP4 expression (P < 0.05).

Conclusion: Our study highlights the role of CSF-BMP4 elevation in glial activation and allodynia during PHN, suggesting a potential therapeutic avenue for future exploration.

Keywords: Astrocyte; Bone morphogenetic protein 4 (BMP4); Drosophila mothers against decapentaplegic protein159 (SMAD159); Glial activation; Iron homeostasis; Microglia; Neuropathic pain (NP); Postherpetic neuralgia (PHN); Signal transducer and activator of transcription 3 (STAT3).