IL-33/ST2 drives inflammatory pain via CCL2 signaling and activation of TRPV1 and TRPM8
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.
Authors
- Siyao Qiu (ORCID: https://orcid.org/0000-0001-9405-4031)
- Zhenhua Qi
- Junting Huang
- Lan Cao (ORCID: https://orcid.org/0000-0002-5817-8050)
- Wen‐Li Mi (ORCID: https://orcid.org/0000-0001-8324-0007)
- Yuting Wang (ORCID: https://orcid.org/0000-0002-9384-8275)
- Denghui Xie (ORCID: https://orcid.org/0000-0001-5414-3152)
- Jingdun Xie (ORCID: https://orcid.org/0000-0002-3820-8435)
- Ruizhen Huang (ORCID: https://orcid.org/0000-0002-2694-5358)
- Mingyu Li (ORCID: https://orcid.org/0000-0003-1217-2929)
- Linjie Wang (ORCID: https://orcid.org/0000-0002-9548-0398)
- Guohao Li
- Tao Luo (ORCID: https://orcid.org/0009-0009-5374-4226)
- Sibo Zhang (ORCID: https://orcid.org/0009-0004-3018-3802)
- Jingyun Zhang (ORCID: https://orcid.org/0000-0002-8577-7956)
- Qingqing Ye (ORCID: https://orcid.org/0000-0002-3262-8965)
- Huaqiao Wang
- Yuge Wang (ORCID: https://orcid.org/0000-0003-3005-6163)
- Yajie An
Institutions
- Guangzhou University of Chinese Medicine (CN)
- Shanghai Medical College of Fudan University (CN)
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Southern Medical University (CN)
- Guangdong Academy of Sciences (CN)
- Sun Yat-sen University Cancer Center (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-05-10
- DOI
- https://doi.org/10.1038/s42003-025-08119-3
- Citations
- 3
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 2.39
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Natural Science Foundation of Guangdong Province
- Fundamental Research Funds for the Central Universities
- Basic and Applied Basic Research Foundation of Guangdong Province