2. Academic Validation
  3. IL-33/ST2 drives inflammatory pain via CCL2 signaling and activation of TRPV1 and TRPM8

IL-33/ST2 drives inflammatory pain via CCL2 signaling and activation of TRPV1 and TRPM8

  • Commun Biol. 2025 May 10;8(1):724. doi: 10.1038/s42003-025-08119-3.
Linjie Wang # 1,  Jingyun Zhang # 1 2,  Shijuan Qiu # 1,  Ruizhen Huang 1,  Yuge Wang 1,  Yuting Wang 1,  Mingyu Li 1,  Qingqing Ye 3,  Sibo Zhang 4,  Zhenhua Qi 3,  Lan Cao 1,  Guohao Li 5 6,  Yajie An 1,  Denghui Xie 5 6,  Wenli Mi 7,  Huaqiao Wang 1,  Tao Luo 8,  Jingdun Xie 9,  Junting Huang 10 11
Affiliations

Affiliations

  • 1 Department of Human Anatomy and Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 2 Central Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Foshan Clinical Medical School, Guangzhou University of Chinese Medicine, Foshan, China.
  • 5 Department of Joint Surgery and Sports Medicine, Center for Orthopedic Surgery, Orthopedic Hospital of Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 6 Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Academy of Orthopedics, Guangzhou, China.
  • 7 Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Institutes of Integrative Medicine, Fudan University, Shanghai, China.
  • 8 Department of Human Anatomy and Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. luot8@mail.sysu.edu.cn.
  • 9 Department of Anesthesiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China. xiejd6@mail.sysu.edu.cn.
  • 10 Department of Human Anatomy and Physiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China. Huangjt56@mail.sysu.edu.cn.
  • 11 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan Medical School, Sun Yat-sen University, Guangzhou, China. Huangjt56@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40348921 DOI: 10.1038/s42003-025-08119-3
Abstract

Innate immunity is the first line of host defense and contributes to pain. However, how innate immune system interacts with sensory neurons to govern pain remains poorly understood. Here, we report that interleukin 33(IL-33) initiates pain hypersensitivity that requires chemokine (C-C motif) ligand 2 (CCL2) secretion from infiltrated macrophages and neutrophils and activation of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential melastatin 8 (TRPM8) channels in sensory neurons. Blocking CCL2 receptor (CCR2) attenuates IL-33- induced and Complete Freund's Adjuvant (CFA)-induced thermal hyperalgesia and blocking TRPV1 and TRPM8 attenuates IL-33-induced mechanical and thermal hypersensitivity and cold allodynia respectively. Furthermore, depletion of macrophages reduces IL-33-induced pain and expression of CCL2 and suppression of tumorigenicity 2 (ST2) in hindpaw skin and inhibition of CCR2 prevents recruitment of macrophages and neutrophils. Our findings reveal an unrecognized neuroimmune crosstalk of IL-33-CCL2 signaling from infiltrated immune cells with TRPV1/TRPM8 in sensory neurons to facilitate pain states.

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