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Immune drivers of pain resolution and protection

Nature Immunology volume 25, pages 2200–2208 (2024)Cite this article

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Abstract

Immune cells are involved in the pathogenesis of pain by directly activating or sensitizing nociceptor sensory neurons. However, because the immune system also has the capacity to self-regulate through anti-inflammatory mechanisms that drive the resolution of inflammation, it might promote pain resolution and prevention. Here, we describe how immune cell-derived cytokines can act directly on sensory neurons to inhibit pain hypersensitivity and how immune-derived endogenous opioids promote analgesia. We also discuss how immune cells support healthy tissue innervation by clearing debris after nerve injury, protecting against axon retraction from target tissues and enhancing regeneration, preventing the development of chronic neuropathic pain. Finally, we review the accumulating evidence that manipulating immune activity positively alters somatosensation, albeit with currently unclear molecular and cellular mechanisms. Exploration of immune-mediated analgesia and pain prevention could, therefore, be important for the development of novel immune therapies for the treatment of clinical pain states.

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Fig. 1: Endogenous immune signaling can reduce peripheral sensitization in nociceptors.
Fig. 2: Opioid peptides released by immune cells act on nociceptors to promote analgesia.
Fig. 3: Immune cells modulate tissue innervation by sensory neurons by promoting nerve repair and protecting against neuropathic pain.

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Acknowledgements

This study was funded by National Institutes of Health (NIH) grants R35 NS105076 to C.J.W., F31NS127357 to S.H. and 1K99AR083482-01 to A.J.

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Author notes

  1. These authors contributed equally: Sara Hakim, Aakanksha Jain.

Authors and Affiliations

  1. F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA

    Sara Hakim, Aakanksha Jain & Clifford J. Woolf

  2. Department of Neurobiology, Harvard Medical School, Boston, MA, USA

    Sara Hakim & Clifford J. Woolf

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  1. Sara Hakim
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  2. Aakanksha Jain
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  3. Clifford J. Woolf
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Contributions

S.H. and A.J. equally contributed to the conceptualization and writing of this manuscript. C.J.W. supervised the organization and scope of the review and contributed to its writing.

Corresponding author

Correspondence to Clifford J. Woolf.

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Competing interests

C.J.W. is a founder of Nocion Therapeutics, Quralis and Blackbox Bio, and a Scientific Advisory Board member of Lundbeck, Axonis and Tafalgie Therapeutics. The remaining authors declare no competing interests.

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Nature Immunology thanks Brian Kim, De’Broski Herbert, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Ioana Staicu, in collaboration with the Nature Immunology team.

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Hakim, S., Jain, A. & Woolf, C.J. Immune drivers of pain resolution and protection. Nat Immunol 25, 2200–2208 (2024). https://doi.org/10.1038/s41590-024-02002-9

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