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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1455771
This article is part of the Research Topic Microglia and tissue macrophages in pain View all articles

Ozone promotes macrophage efferocytosis and alleviates neuropathic pain by activating the AMPK/Gas6-MerTK/SOCS3 signaling pathway

Provisionally accepted
Shirong Ruan Shirong Ruan 1Rumeng Jia Rumeng Jia 1Liang Hu Liang Hu 1Yuge Liu Yuge Liu 2Qingyan Tian Qingyan Tian 1Kunmao Jiang Kunmao Jiang 1Xinyue Xia Xinyue Xia 1Tao Xueyou Tao Xueyou 3Yinbing Pan Yinbing Pan 4Fan Hu Fan Hu 1Wen-Tao Liu Wen-Tao Liu 1,5*
  • 1 Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, Nanjing, Liaoning Province, China
  • 2 The Friendship Hospital of Ili Kazakh Autonomous Prefecture, Yining, Xinjiang, China
  • 3 Department of Pathology, Yangzhou Maternity and Child Health Care Hospital, Yangzhou, Jiangsu Province, China
  • 4 Department of Anesthesiology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
  • 5 Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China

The final, formatted version of the article will be published soon.

    Neuropathic pain (NPP) is a multifaceted pain syndrome that occurs as a consequence of physical injury or underlying diseases, with an incidence rate of 7%-10%, NPP poses a significant clinical challenge as current treatment options are ineffective. The accumulation of apoptotic cells and neuroinflammation play crucial roles in the pathological mechanisms of NPP. Here, we aim to investigate strategies for effectively clearing apoptotic cells and provide therapeutic interventions for NPP. CCI mice were treated with different concentrations of ozone (15μg, 30μg, 45μg) to investigate the effects on the accumulation of apoptotic cells and neuroinflammation. In vitro, the phagocytic function of BMDM towards apoptotic neutrophils after ozone treatment was examined. We found ozone at a concentration of 30μg significantly alleviated mechanical hypersensitivity in CCI mice and ozone significantly upregulates the phagocytic activity of BMDM. Furthermore, we investigated the mechanisms and found ozone could activate AMPK, upregulate Gas6 (but not Protein S), activate MerTK (a key receptor involved in apoptosis), and enhance the phagocytic function of BMDM towards apoptotic neutrophils. It caused the promotion of SOCS3 expression and the suppression of inflammatory factors IL-1β, IL-6, and TNF-a. Interestingly, the effect of ozone in alleviating CCI-induced pain was abolished by the AMPK inhibitor CC and the MerTK receptor inhibitor UNC2541. In conclusion, Ozone facilitated macrophage clearance of apoptotic cells, decreased neuroinflammation by activation of p-AMPK/Gas6/MerTK/SOCS3 signaling pathway, which may become an effective therapeutic approach for neuropathic pain after further clinical validation.

    Keywords: neuropathic pain, Ozone, macrophage, Efferocytosis, MERTK, socs3, Neuroinflammation

    Received: 27 Jun 2024; Accepted: 28 Oct 2024.

    Copyright: © 2024 Ruan, Jia, Hu, Liu, Tian, Jiang, Xia, Xueyou, Pan, Hu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Wen-Tao Liu, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, China

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