In a recent paper published in Nature, Lu et al.1 reveal a pivotal role of Nav1.8+ nociceptor-released neuropeptide calcitonin gene-related peptide (CGRP) in modulating the activities of myeloid cells during skin and muscle injury repair. This study demonstrated the significant impact of sensory neurons on injury-induced inflammation and wound healing.
Tissue injury and subsequent repair pose substantial clinical challenges in the form of chronic wounds or fibrotic scarring. In such clinical circumstances, wound healing does not progress through the normal sequential phases of hemostasis, inflammation, proliferation and remodeling. Specifically, dysregulation of myeloid cells (monocytes, macrophages, neutrophils) is directly associated with various clinical forms of maladaptive wound healing, ranging from non-healing wounds to tissue fibrosis and excessive scarring.
Although the peripheral nervous system has not received as much attention relative to endothelial/vascular and immune cell components, the role of peripheral nerves in tissue repair has not been entirely neglected. Studies conducted in animal models over 60 years ago, involving experimental resection of peripheral nerves, have demonstrated a connection between nerve endings and skin wound healing.2 Not only neurons, but also peripheral glial cells such as Schwann cells are instrumental in wound healing by undergoing de-differentiation, proliferation, and releasing pro-healing paracrine factors, such as transforming growth factor-β.3
Lu et al.1 uncovers an additional critical role of the nerve endings specifically tasked with sensing pain (Nav1.8+ nociceptors) in influencing myeloid cells during tissue injury. Nociceptors are specialized sensory neurons tasked with pain perception, and they enable the organism to detect inflammation, extreme temperature changes, and mechanical pressure. Leveraging Nav1.8cre;Rosa26DTA double-transgenic mice, the authors were able to selectively deplete NaV1.8+ dorsal root ganglion neurons via diphtheria toxin-mediated cell death, and employed two injury models: dorsal skin full-thickness wounds and upper thigh quadriceps muscle loss. Their findings in rodents demonstrate that the absence of NaV1.8 nociceptors significantly delay skin wound closure and diminished muscle regeneration while increasing fibrotic scars.
Employing Nav1.8cre;Rosa26tdT mice to track nociceptors with red fluorescence protein, the researchers pinpointed that NaV1.8+ neurons were activated upon tissue injury, and nerve endings extend into the granulation tissue formed after skin and muscle injuries, releasing a neuropeptide called CGRP. Notably, non-activated nociceptors do not secret CGRP during homeostatic non-injured conditions. CGRP acts as a ligand for receptor activity modifying protein (RAMP1) expressed on myeloid cells. Mice with reconstituted bone marrow cells deficient in RAMP1 exhibit severe impairment in skin and muscle healing, mirroring the effects observed in NaV1.8 nociceptor-ablated mice. Furthermore, the authors confirmed that sensory neuron-derived CGRP promoted tissue healing by directly modulating myeloid cells. This was verified in LysMcre;Ramp1fl/fl mice, where LysM+ myeloid cells lack RAMP1 expression. Strikingly, these mice exhibited similar healing impairment as observed in nociceptor-deletion models. Depletion of nociceptors in Nav1.8cre;Rosa26DTA mice led to elevated numbers of neutrophils and pro-inflammatory macrophages in the injury sites, and to delayed wound healing. Through in vitro assays and an adoptive transfer model with Ramp1-/- myeloid cells, the authors further demonstrated that CGRP signaling regulated myeloid cell dynamics in many ways, including reducing myeloid cell recruitment and augmenting cell death, enhancing clearance of debris/dead cells by efferocytosis, and promoting macrophage polarization needed for wound healing to progress. These effects were shown to be further amplified by the autocrine and paracrine release of thrombospondin-1 by myeloid cells (summarized in Fig. 1).
Leveraging these findings linking nociceptor-CGRP to inflammation, the authors developed a pre-clinical approach that ensures sustained release of CGRP at the wound site by fusing CGRP with an ECM-binding sequence (eCGRP), followed by a plasmin-sensitive sequence to facilitate retention and gradual release of CGRP at the injury site. Application of eCGRP, either topically to wounds or via injection into muscle using a fibrin hydrogel, successfully rescued the healing deficits observed in nociceptor-depleted Nav1.8cre;Rosa26DTA mice. Finally, the efficacy of eCGRP was validated in a clinically relevant db/db mice, a leptin receptor-deficient mouse model that exhibits type 2 diabetes with peripheral neuropathy. Treatment with eCGRP markedly improved wound closure and muscle regeneration in the diabetic setting.
Recent research has uncovered additional critical roles of sensory neurons in immune regulation. For instance, Hanc et al. demonstrated that nociceptors can modulate dendritic cell functions through various mechanisms to maintain skin barrier function, including the release of neuropeptide CGRP and chemokine CCL2, as well as depolarization of DC cell membranes via calcium fluxes.4 Similarly, in the lung models of inflammation, vagal sensory neurons release CGRPβ via JAK1 activation, which can suppress the function of group 2 innate lymphoid cells and mitigate allergic inflammation.5
Clinical indications further illustrate the link between neuro-inflammation and wound healing. For example, peripheral neuropathies pose significant challenges to skin wound healing, notably exemplified in conditions such as diabetic foot ulcers (DFUs). Clinical classification of DFUs often revolves around symptoms of neuropathies and vascular pathologies. While the mechanistic and therapeutic aspects of vascular pathologies with deficient circulation have been extensively explored, progress in understanding the impact of neuropathies on DFUs has been slow. Further links between neuro-inflammation and wound healing are also evident in other clinical scenarios. For example, it is widely recognized, albeit often unreported, that paraplegic patients experience markedly delayed wound healing. A second example lies in current clinical practice, where the delaying effect of denervation on skin incision healing is demonstrated in cutaneous wounds involving fasciocutaneous- or myocutaneous-free microvascular tissue. In these cases, autologous tissue containing skin, blood vessels, and nerve fibers is surgically excised and microsurgically transplanted into tissue defects following tumor resection or trauma, without the reconnection of concomitant sensory nerve fibers.
Therefore, innovative approaches that bypass or reactivate the neuro-immune axis in wounds, such as with eCGRP presented in Lu et al., holds promise for advancing therapeutic strategies in the context of impaired wound healing across a range of clinical settings.
References
Lu, Y. Z. et al. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature 628, 604–611 (2024).
Sandberg, N. & Zederfeldt, B. Delayed effect of denervation on the healing of skin incisions in the rabbit. Acta Chir. Scand. 121, 111–117 (1961).
Parfejevs, V. et al. Injury-activated glial cells promote wound healing of the adult skin in mice. Nat. Commun. 9, 236 (2018).
Hanc, P. et al. Multimodal control of dendritic cell functions by nociceptors. Science 379, eabm5658 (2023).
Tamari, M. et al. Sensory neurons promote immune homeostasis in the lung. Cell 187, 44.e17–61.e17 (2024).
Acknowledgements
This commentary was supported by funds from the European Research Council Consolidator Grant (ERC-CoG 819933), the LEO Foundation (LF-OC-21-000835), the European Foundation for the Study of Diabetes Anniversary Fund Programme 2021 (EFSD #98201), the Marie Curie Innovative Training Network (955722 SkinTERM), and the German Research Foundation (CRC-359 PILOT).
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D.J. wrote the initial draft of the manuscript. H.-G.M. and Y.R. supervised and revised the manuscript. All authors have reviewed and approved the article.
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Jiang, D., Machens, HG. & Rinkevich, Y. Sensory neurons: unveiling the symphony of wound healing. Sig Transduct Target Ther 9, 177 (2024). https://doi.org/10.1038/s41392-024-01880-7
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DOI: https://doi.org/10.1038/s41392-024-01880-7