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Background <p>Musculoskeletal injuries are a frequent occurrence in sports medicine and rehabilitation, and their healing process needs an accurate response from inflammation. Recent studies show that sensory neurons play a critical role in tissue repair through neuropeptides, which is quite different from their usual function as simple pain detectors. The current review summarizes studies conducted during the last ten years concerning neuroimmune crosstalk mechanisms in musculoskeletal injury healing, in which the role of sensory neurons in macrophage polarization is emphasized.</p> Methods <p>We reviewed preclinical studies on the neuro-immune interaction after musculoskeletal injury, emphasizing the CGRP-RAMP1-thrombospondin-1 axis and parallel pathways including TGF-β-mediated macrophage specification and TAFA4-IL-10 signaling. Based on rodent data regarding skin wounds, muscle injury, peripheral nerve injury, and other pertinent models, a theoretical model relating mechanical loading and neuroimmune inhibition was established.</p> Results <p>CGRP-RAMP1-Thrombospondin 1 signaling pathway has been identified in preclinical studies as an candidate pathway for shifting macrophages from a pro-inflammatory (M1) to a pro-repair (M2) phenotype, hence balancing the process of pathogen clearance against tissue repair process. Parallel systems, such as TGF-β-mediated macrophage specification and TAFA4-IL-10 signaling, provide redundancy and robustness. Controlled loading, as seen with active recovery, causes stimulation of sensory neuron terminals, leads to the release of neuropeptides, triggers the neuroimmune braking process, and promotes proper M1-to-M2 conversion. The understanding of these mechanisms explains why patients have always been advised to undertake active recovery rather than rest following tendon/ligament damage.</p> Conclusion <p>This review proposes a new conceptual framework in which the neuroimmune axis may serve as a key controller of musculoskeletal repair. These biological mechanisms offer a potential explanation for the medical choice of active recovery over complete rest following specific injuries; nevertheless, there is no direct evidence in humans, and this theory needs to be tested in human studies.</p>

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Neuroimmune braking mechanisms in exercise-related musculoskeletal injury: from nociceptors to tissue regeneration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月13日

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  • Enli Xie,
  • Yushan He,
  • Tainan Cao,
  • Changchun Li,
  • Zhiming Wang

摘要

Background

Musculoskeletal injuries are a frequent occurrence in sports medicine and rehabilitation, and their healing process needs an accurate response from inflammation. Recent studies show that sensory neurons play a critical role in tissue repair through neuropeptides, which is quite different from their usual function as simple pain detectors. The current review summarizes studies conducted during the last ten years concerning neuroimmune crosstalk mechanisms in musculoskeletal injury healing, in which the role of sensory neurons in macrophage polarization is emphasized.

Methods

We reviewed preclinical studies on the neuro-immune interaction after musculoskeletal injury, emphasizing the CGRP-RAMP1-thrombospondin-1 axis and parallel pathways including TGF-β-mediated macrophage specification and TAFA4-IL-10 signaling. Based on rodent data regarding skin wounds, muscle injury, peripheral nerve injury, and other pertinent models, a theoretical model relating mechanical loading and neuroimmune inhibition was established.

Results

CGRP-RAMP1-Thrombospondin 1 signaling pathway has been identified in preclinical studies as an candidate pathway for shifting macrophages from a pro-inflammatory (M1) to a pro-repair (M2) phenotype, hence balancing the process of pathogen clearance against tissue repair process. Parallel systems, such as TGF-β-mediated macrophage specification and TAFA4-IL-10 signaling, provide redundancy and robustness. Controlled loading, as seen with active recovery, causes stimulation of sensory neuron terminals, leads to the release of neuropeptides, triggers the neuroimmune braking process, and promotes proper M1-to-M2 conversion. The understanding of these mechanisms explains why patients have always been advised to undertake active recovery rather than rest following tendon/ligament damage.

Conclusion

This review proposes a new conceptual framework in which the neuroimmune axis may serve as a key controller of musculoskeletal repair. These biological mechanisms offer a potential explanation for the medical choice of active recovery over complete rest following specific injuries; nevertheless, there is no direct evidence in humans, and this theory needs to be tested in human studies.