The roles of the nerve-immune axis in modulating bone regeneration

Abstract

Bone is highly innervated, and its regeneration is significantly nerve-dependent. Extensive evidence suggests that the nervous system plays an active role in bone metabolism and development by modulating osteoblast and osteoclast activity. However, the majority of research to date has focused on the direct effects of peripheral nerves and their neurotransmitters on bone regeneration. Emerging studies have begun to reveal a more intricate role of nerves in regulating the immune microenvironment, which is crucial for bone regeneration. This review summarizes how nerves influence bone regeneration through modulation of the immune microenvironment. We first discuss the changes in peripheral nerves during the regenerative process. We then describe conduction and paracrine pathways through which nerves affect the osteogenic immune microenvironment, emphasizing nerves, neural factors, and their impacts. Our goal is to deepen the understanding of the nerve-immune axis in bone regeneration. A better grasp of how nerves influence the osteogenic immune microenvironment may lead to new strategies that integrate the nervous, immune, and skeletal systems to promote bone regeneration.

References

[1] Li J, et al.. Emerging roles of nerve-bone axis in modulating skeletal system. Med. Res. Rev., 2024, 44: 1867-1903

[2] Sudiwala S, Knox SM. The emerging role of cranial nerves in shaping craniofacial development. Genesis, 2019, 57: e23282

[3] Tomlinson RE, et al.. NGF-TrkA signaling by sensory nerves coordinates the vascularization and ossification of developing endochondral bone. Cell Rep., 2016, 16: 2723-2735

[4] Salhotra A, Shah HN, Levi B, Longaker MT. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol., 2020, 21: 696-711

[5] Shi L, et al.. Function study of vasoactive intestinal peptide on chick embryonic bone development. Neuropeptides, 2020, 83 102077

[6] Chen Y, Guo B, Ma G, Cao H. Sensory nerve regulation of bone homeostasis: Emerging therapeutic opportunities for bone-related diseases. Ageing Res. Rev., 2024, 99: 102372

[7] Da Silva MR, et al.. Neuroimmune expression in hip osteoarthritis: a systematic review. BMC Musculoskelet. Disord., 2017, 18 394

[8] Dong T, et al.. Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis. Int. Orthop., 2015, 39: 1237-1243

[9] Li W, Long X, Jiang S, Li Y, Fang W. Histamine and substance P in synovial fluid of patients with temporomandibular disorders. J. Oral. Rehabil., 2015, 42: 363-369

[10] Nakasa T, Ishikawa M, Takada T, Miyaki S, Ochi M. Attenuation of cartilage degeneration by calcitonin gene-related paptide receptor antagonist via inhibition of subchondral bone sclerosis in osteoarthritis mice. J. Orthop. Res., 2016, 34: 1177-1184

[11] Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. J. Headache Pain, 2017, 18 34

[12] Wang H, et al.. Increasing expression of substance P and calcitonin gene-related peptide in synovial tissue and fluid contribute to the progress of arthritis in developmental dysplasia of the hip. Arthritis Res. Ther., 2015, 17: 4

[13] Apel PJ, et al.. Effect of selective sensory denervation on fracture-healing: an experimental study of rats. J. Bone Jt. Surg. Am., 2009, 91: 2886-2895

[14] Tao R, et al.. Hallmarks of peripheral nerve function in bone regeneration. Bone Res., 2023, 11: 6

[15] Einhorn TA, Gerstenfeld LC. Fracture healing: mechanisms and interventions. Nat. Rev. Rheumatol., 2015, 11: 45-54

[16] Loi F, et al.. Inflammation, fracture and bone repair. Bone, 2016, 86: 119-130

[17] Hurst SM, et al.. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity, 2001, 14: 705-714

[18] Torres HM, Arnold KM, Oviedo M, Westendorf JJ, Weaver SR. Inflammatory processes affecting bone health and repair. Curr. Osteoporos. Rep., 2023, 21: 842-853

[19] Schmidt-Bleek K, et al.. Inflammatory phase of bone healing initiates the regenerative healing cascade. Cell Tissue Res., 2012, 347: 567-573

[20] Lu Y-Z, et al.. CGRP sensory neurons promote tissue healing via neutrophils and macrophages. Nature, 2024, 628: 604-611

[21] Zhang Y, et al.. Role of VIP and sonic hedgehog signaling pathways in mediating epithelial wound healing, sensory nerve regeneration, and their defects in diabetic corneas. Diabetes, 2020, 69: 1549-1561

[22] Xu Y, et al.. Inferior alveolar nerve transection disturbs innate immune responses and bone healing after tooth extraction. Ann. N. Y. Acad. Sci., 2019, 1448: 52-64

[23] Liu W, et al.. Traumatic brain injury stimulates sympathetic tone-mediated bone marrow myelopoiesis to favor fracture healing. Signal Transduct. Target. Ther., 2023, 8: 260

[24] Albright TD, Jessell TM, Kandel ER, Posner MI. Neural science: a century of progress and the mysteries that remain. Neuron, 2000, 25: S1-S55

[25] Mach DB, et al.. Origins of skeletal pain: sensory and sympathetic innervation of the mouse femur. Neuroscience, 2002, 113: 155-166

[26] Wehrwein EA, Orer HS, Barman SM. Overview of the anatomy, physiology, and pharmacology of the autonomic nervous system. Compr. Physiol., 2016, 6: 1239-1278

[27] Brazill JM, Beeve AT, Craft CS, Ivanusic JJ, Scheller EL. Nerves in bone: evolving concepts in pain and anabolism. J. Bone Miner. Res., 2019, 34: 1393-1406

[28] Clarke B. Normal bone anatomy and physiology. Clin. J. Am. Soc. Nephrol., 2008, 3: S131-S139

[29] Evans SF, Chang H, Knothe Tate ML. Elucidating multiscale periosteal mechanobiology: a key to unlocking the smart properties and regenerative capacity of the periosteum?. Tissue Eng. Part B Rev., 2013, 19: 147-159

[30] Scheib J, Höke A. Advances in peripheral nerve regeneration. Nat. Rev. Neurol., 2013, 9: 668-676

[31] Rigoni M, Negro S. Signals orchestrating peripheral nerve repair. Cells, 2020, 9: 1768

[32] Burnett MG, Zager EL. Pathophysiology of peripheral nerve injury: a brief review. Neurosurg. Focus, 2004, 16: 1-7

[33] Li Z, et al.. Fracture repair requires TrkA signaling by skeletal sensory nerves. J. Clin. Investig., 2019, 129: 5137-5150

[34] Mantyh PW. The neurobiology of skeletal pain. Eur. J. Neurosci., 2014, 39: 508-519

[35] Chartier SR, et al.. Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain, 2014, 155: 2323-2336

[36] Charles JF, Nakamura MC. Bone and the innate immune system. Curr. Osteoporos. Rep., 2014, 12: 1-8

[37] Wang H, et al.. T cell related osteoimmunology in fracture healing: potential targets for augmenting bone regeneration. J. Orthop. Transl., 2025, 51: 82-93

[38] Mi B, et al.. Macrophage-mediated fracture healing: unraveling molecular mechanisms and therapeutic implications using hydrogel-based interventions. Biomaterials, 2024, 305 122461

[39] Su N, Villicana C, Yang F. Immunomodulatory strategies for bone regeneration: a review from the perspective of disease types. Biomaterials, 2022, 286: 121604

[40] Bi Z, et al.. Macrophage-mediated immunomodulation in biomaterial-assisted bone repair: molecular insights and therapeutic prospects. Chem. Eng. J., 2024, 488: 150631

[41] Niu Y, Wang Z, Shi Y, Dong L, Wang C. Modulating macrophage activities to promote endogenous bone regeneration: biological mechanisms and engineering approaches. Bioact. Mater., 2021, 6: 244-261

[42] Huang D, et al.. Remotely temporal scheduled macrophage phenotypic transition enables optimized immunomodulatory bone regeneration. Small, 2022, 18 2203680

[43] Wang Y, et al.. M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator. Bioact. Mater., 2023, 28: 273-283

[44] Huang C, et al.. M2 macrophage-derived exosomes carry miR-142-3p to restore the differentiation balance of irradiated BMMSCs by targeting TGF-β1. Mol. Cell. Biochem., 2024, 479: 993-1010

[45] Li Z, Wang Y, Li S, Li Y. Exosomes derived From M2 macrophages facilitate osteogenesis and reduce adipogenesis of BMSCs. Front. Endocrinol., 2021, 12: 680328

[46] Liu J, et al.. M2 macrophage-derived exosomal miR-486-5p influences the differentiation potential of bone marrow mesenchymal stem cells and osteoporosis. Aging, 2023, 15: 9499-9520

[47] Luo X, et al.. MicroRNA-21a-5p-modified macrophage exosomes as natural nanocarriers promote bone regeneration by targeting GATA2. Regen. Biomater., 2023, 10: rbad075

[48] Pu P, et al.. Mechanical force induces macrophage-derived exosomal UCHL3 promoting bone marrow mesenchymal stem cell osteogenesis by targeting SMAD1. J. Nanobiotechnology, 2023, 21 88

[49] Chi Z, et al.. Gasdermin D-mediated metabolic crosstalk promotes tissue repair. Nature, 2024, 634: 1168-1177

[50] Hanoun M, Maryanovich M, Arnal-Estapé A, Frenette PS. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron, 2015, 86: 360-373

[51] Williams MC, Ivanusic JJ. Evidence for the involvement of the spinoparabrachial pathway, but not the spinothalamic tract or post-synaptic dorsal column, in acute bone nociception. Neurosci. Lett., 2008, 443: 246-250

[52] Saper CB, Lowell BB. The hypothalamus. Curr. Biol., 2014, 24: R1111-R1116

[53] Holt MK, et al.. Synaptic inputs to the mouse dorsal vagal complex and its resident preproglucagon neurons. J. Neurosci., 2019, 39: 9767-9781

[54] Chiang MC, et al.. Parabrachial complex: a hub for pain and aversion. J. Neurosci., 2019, 39: 8225-8230

[55] Livneh Y, et al.. Homeostatic circuits selectively gate food cue responses in insular cortex. Nature, 2017, 546: 611-616

[56] Suarez AN, Liu CM, Cortella AM, Noble EE, Kanoski SE. Ghrelin and orexin interact to increase meal size through a descending hippocampus to hindbrain signaling pathway. Biol. Psychiatry, 2020, 87: 1001-1011

[57] Phillips JW, et al.. A repeated molecular architecture across thalamic pathways. Nat. Neurosci., 2019, 22: 1925-1935

[58] Ran C, Boettcher JC, Kaye JA, Gallori CE, Liberles SD. A brainstem map for visceral sensations. Nature, 2022, 609: 320-326

[59] Ivanusic JJ, Sahai V, Mahns DA. The cortical representation of sensory inputs arising from bone. Brain Res., 2009, 1269: 47-53

[60] Takeda S, et al.. Leptin regulates bone formation via the sympathetic nervous system. Cell, 2002, 111: 305-317

[61] Wee NKY, Lorenz MR, Bekirov Y, Jacquin MF, Scheller EL. Shared autonomic pathways connect bone marrow and peripheral adipose tissues across the central neuraxis. Front. Endocrinol., 2019, 10: 668

[62] Dénes Á, et al.. Central autonomic control of the bone marrow: multisynaptic tract tracing by recombinant pseudorabies virus. Neuroscience, 2005, 134: 947-963

[63] Bajayo A, et al.. Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual. Proc. Natl. Acad. Sci. USA, 2012, 109: 15455-15460

[64] Hu B, et al.. Sensory nerves regulate mesenchymal stromal cell lineage commitment by tuning sympathetic tones. J. Clin. Invest., 2020, 130: 3483-3498

[65] Chen H, et al.. Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis. Nat. Commun., 2019, 10 181

[66] Bakker AD, Joldersma M, Klein-Nulend J, Burger EH. Interactive effects of PTH and mechanical stress on nitric oxide and PGE2 production by primary mouse osteoblastic cells. Am. J. Physiol. -Endocrinol. Metab., 2003, 285: E608-E613

[67] Coetzee M, Haag M, Claassen N, Kruger MC. Stimulation of prostaglandin E2 (PGE2) production by arachidonic acid, oestrogen and parathyroid hormone in MG-63 and MC3T3-E1 osteoblast-like cells. Prostaglandins Leukot. Essent. Fat. Acids, 2005, 73: 423-430

[68] Sumitani K, Kawata T, Yoshimoto T, Yamamoto S, Kumegawa M. Fatty acid cyclooxygenase activity stimulated by transforming growth factor-beta in mouse osteoblastic cells (MC3T3-E1). Arch. Biochem. Biophys., 1989, 270: 588-595

[69] Vance J, Galley S, Liu DF, Donahue SW. Mechanical stimulation of MC3T3 osteoblastic cells in a bone tissue-engineering bioreactor enhances prostaglandin E2 release. Tissue Eng., 2005, 11: 1832-1839

[70] Pinho-Ribeiro FA, Verri WA, Chiu IM. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol., 2017, 38: 5-19

[71] Terenzio M, et al.. Locally translated mTOR controls axonal local translation in nerve injury. Science, 2018, 359: 1416-1421

[72] Talbot S, Foster SL, Woolf CJ. Neuroimmunity: physiology and pathology. Annu. Rev. Immunol., 2016, 34: 421-447

[73] Schiller M, Ben-Shaanan TL, Rolls A. Neuronal regulation of immunity: why, how and where?. Nat. Rev. Immunol., 2021, 21: 20-36

[74] McMahon SB, Russa FL, Bennett DLH. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat. Rev. Neurosci., 2015, 16: 389-402

[75] Lopez-Verrilli MA, Picou F, Court FA. Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia, 2013, 61: 1795-1806

[76] Wei Z, et al.. Proteomics analysis of Schwann cell-derived exosomes: a novel therapeutic strategy for central nervous system injury. Mol. Cell. Biochem., 2019, 457: 51-59

[77] Chiu IM, Von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat. Neurosci., 2012, 15: 1063-1067

[78] Dianzani C, Collino M, Lombardi G, Garbarino G, Fantozzi R. Substance P increases neutrophil adhesion to human umbilical vein endothelial cells. Br. J. Pharmacol., 2003, 139: 1103-1110

[79] Wan Q, et al.. Crosstalk between bone and nerves within bone. Adv. Sci., 2021, 8: 2003390

[80] Zhang Q, et al.. CGRP-modulated M2 macrophages regulate osteogenesis of MC3T3-E1 via Yap1. Arch. Biochem. Biophys., 2021, 697: 108697

[81] Offley SC, et al.. Capsaicin-sensitive sensory neurons contribute to the maintenance of trabecular bone integrity. J. Bone Miner. Res., 2005, 20: 257-267

[82] Němec I, Smrčka V, Pokorný J. The effect of sensory innervation on the inorganic component of bones and teeth; experimental denervation—review. Prague Med. Rep., 2018, 119: 137-147

[83] Hoffman DR, Tade WH. Improved technique for sectioning the inferior alveolar nerve in rats. J. Dent. Res., 1972, 51: 668

[84] Liu J, et al.. TRPV1⁺ sensory nerves modulate corneal inflammation after epithelial abrasion via RAMP1 and SSTR5 signaling. Mucosal Immunol., 2022, 15: 867-881

[85] Zheng G, et al.. Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury. J. Nanobiotechnology, 2024, 22 399

[86] Yamashita A, et al.. RAMP1 signaling mitigates acute lung injury by distinctively regulating alveolar and monocyte-derived macrophages. Int. J. Mol. Sci., 2024, 25: 10107

[87] Zhang R, et al.. CGRP alleviates lipopolysaccharide-induced ARDS inflammation via the HIF-1α signaling pathway. Clin. Sci., 2025, 139: 373-387

[88] Yuan K, et al.. Sensory nerves promote corneal inflammation resolution via CGRP mediated transformation of macrophages to the M2 phenotype through the PI3K/AKT signaling pathway. Int. Immunopharmacol., 2022, 102: 108426

[89] Tao J, Wang X, Xu J. Expression of CGRP in the trigeminal ganglion and its effect on the polarization of macrophages in rats with temporomandibular arthritis. Cell. Mol. Neurobiol., 2024, 44: 22

[90] Fattori V, et al.. Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice. Sci. Transl. Med., 2024, 16 eadk8230

[91] Pinho-Ribeiro FA, et al.. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell, 2018, 173: 1083-1097.e22

[92] Liu H, et al.. From pain to meningitis: bacteria hijack nociceptors to promote meningitis. Front. Immunol., 2025, 15: 1515177

[93] Baral P, et al.. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med., 2018, 24: 417-426

[94] Fang X, et al.. Staphylococcus aureus tames nociceptive neurons to suppress synovial macrophage responses for sustained infection in septic arthritis. Adv. Sci., 2025, 12: 2409251

[95] Xu K, et al.. Selective promotion of sensory innervation-mediated immunoregulation for tissue repair. Sci. Adv., 2025, 11 eads9581

[96] Wang J, et al.. Cerebral ischemia increases bone marrow CD4⁺CD25⁺FoxP3⁺ regulatory T cells in mice via signals from sympathetic nervous system. Brain Behav. Immun., 2015, 43: 172-183

[97] Niedermair T, Straub RH, Brochhausen C, Grässel S. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice. Int. J. Mol. Sci., 2020, 21: 405

[98] Chapleau MW, Hajduczok G, Abboud FM. Mechanisms of resetting of arterial baroreceptors: an overview. Am. J. Med. Sci., 1988, 295: 327-334

[99] Franchini KG, Krieger EM. Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN. J. Auton. Nerv. Syst., 1993, 42: 63-69

[100] Huston JM, et al.. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J. Exp. Med., 2006, 203: 1623-1628

[101] Pavlov VA, et al.. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. USA, 2006, 103: 5219-5223

[102] Huston JM, et al.. Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Crit. Care Med., 2007, 35: 2762-2768

[103] Levine YA, et al.. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One, 2014, 9: e104530

[104] Udit S, Blake K, Chiu IM. Somatosensory and autonomic neuronal regulation of the immune response. Nat. Rev. Neurosci., 2022, 23: 157-171

[105] Ribeiro AB, et al.. Carotid sinus nerve stimulation attenuates alveolar bone loss and inflammation in experimental periodontitis. Sci. Rep., 2020, 10 19258

[106] Schlundt C, et al.. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone, 2018, 106: 78-89

[107] Raggatt LJ, et al.. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am. J. Pathol., 2014, 184: 3192-3204

[108] Chan JK, et al.. Low-dose TNF augments fracture healing in normal and osteoporotic bone by up-regulating the innate immune response. EMBO Mol. Med., 2015, 7: 547-561

[109] Chow SK-H, et al.. Modulating macrophage polarization for the enhancement of fracture healing, a systematic review. J. Orthop. Transl., 2022, 36: 83-90

[110] Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M. Macrophage plasticity and polarization in tissue repair and remodelling. J. Pathol., 2013, 229: 176-185

[111] Pajarinen J, et al.. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials, 2019, 196: 80-89

[112] Xu J, et al.. The effects of calcitonin gene-related peptide on bone homeostasis and regeneration. Curr. Osteoporos. Rep., 2020, 18: 621-632

[113] Steenbergh PM, et al.. Structure and expression of the human calcitonin/CGRP genes. FEBS Lett., 1986, 209: 97-103

[114] Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiol. Rev., 2023, 103: 1565-1644

[115] Assas BM, Pennock JI, Miyan JA. Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis. Front. Neurosci., 2014, 8: 23

[116] Yuan Y, et al.. Deficiency of calcitonin gene-related peptide affects macrophage polarization in osseointegration. Front. Physiol., 2020, 11: 733

[117] Kong Q, et al.. Calcitonin gene-related peptide-modulated macrophage phenotypic alteration regulates angiogenesis in early bone healing. Int. Immunopharmacol., 2024, 130: 111766

[118] Cao YQ, et al.. Primary afferent tachykinins are required to experience moderate to intense pain. Nature, 1998, 392: 390-394

[119] Fx L, et al.. The role of substance P in the regulation of bone and cartilage metabolic activity. Front. Endocrinol, 2020, 11: 77

[120] Redkiewicz P. The regenerative potential of substance P. Int. J. Mol. Sci., 2022, 23: 750

[121] Leal EC, et al.. Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype. Am. J. Pathol., 2015, 185: 1638-1648

[122] Sipka A, Langner K, Seyfert H-M, Schuberth H-J. Substance P alters the in vitro LPS responsiveness of bovine monocytes and blood-derived macrophages. Vet. Immunol. Immunopathol., 2010, 136: 219-226

[123] Lim JE, Chung E, Son YA. neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFN. Sci. Rep., 2017, 7 9417

[124] Park JH, Kim S, Hong HS, Son Y. Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells. Wound Repair Regen., 2016, 24: 337-348

[125] Zhou Z, et al.. Substance P promote macrophage M2 polarization to attenuate secondary lymphedema by regulating NF-κB/NLRP3 signaling pathway. Peptides, 2023, 168 171045

[126] Song L, et al.. A Bibliometric and knowledge-map analysis of macrophage polarization in atherosclerosis from 2001 to 2021. Front. Immunol., 2022, 13: 910444

[127] Xu X, Wang Y, Li Y, Zhang B, Song Q. The future landscape of macrophage research in cardiovascular disease: a bibliometric analysis. Curr. Probl. Cardiol., 2022, 47: 101311

[128] Jiao Y, et al.. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit. Care, 2021, 25 356

[129] Yazdani U, Terman JR. The semaphorins. Genome Biol., 2006, 7 211

[130] Ji J-D, Park-Min K-H, Ivashkiv LB. Expression and function of semaphorin 3A and its receptors in human monocyte-derived macrophages. Hum. Immunol., 2009, 70: 211-217

[131] Satomi K, Nishimura K, Igarashi K. Semaphorin 3A protects against alveolar bone loss during orthodontic tooth movement in mice with periodontitis. J. Periodontal Res., 2022, 57: 991-1002

[132] Wang W, et al.. The neuropeptide vasoactive intestinal peptide levels in serum are inversely related to disease severity of postmenopausal osteoporosis: a cross-sectional study. Genet. Test. Mol. Biomark., 2019, 23: 480-486

[133] Juhász T, Helgadottir SL, Tamás A, Reglődi D, Zákány R. PACAP and VIP signaling in chondrogenesis and osteogenesis. Peptides, 2015, 66: 51-57

[134] Cherruau M, Morvan FO, Schirar A, Saffar JL. Chemical sympathectomy-induced changes in TH-, VIP-, and CGRP-immunoreactive fibers in the rat mandible periosteum: influence on bone resorption. J. Cell. Physiol., 2003, 194: 341-348

[135] Deng G, Jin L. The effects of vasoactive intestinal peptide in neurodegenerative disorders. Neurol. Res., 2017, 39: 65-72

[136] Wang H, et al.. Nanoparticle-driven tendon repair: role of vasoactive intestinal peptide in immune modulation and stem cell enhancement. ACS Nano, 2025, 19: 13871-13888

[137] Azevedo M, et al.. Macrophage polarization and alveolar bone healing outcome: despite a significant M2 polarizing effect, VIP and PACAP treatments present a minor impact in alveolar bone healing in homeostatic conditions. Front. Immunol., 2021, 12: 782566

[138] Lundberg P, et al.. Vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide receptor subtypes in mouse calvarial osteoblasts: presence of VIP-2 receptors and differentiation-induced expression of VIP-1 receptors. Endocrinology, 2001, 142: 339-347

[139] Mukohyama H, Ransjö M, Taniguchi H, Ohyama T, Lerner UH. The inhibitory effects of vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide on osteoclast formation are associated with upregulation of osteoprotegerin and downregulation of RANKL and RANK. Biochem. Biophys. Res. Commun., 2000, 271: 158-163

[140] Ransjö M, Lie A, Mukohyama H, Lundberg P, Lerner UH. Microisolated mouse osteoclasts express VIP-1 and PACAP receptors. Biochem. Biophys. Res. Commun., 2000, 274: 400-404

[141] Haffner-Luntzer M, et al.. Chronic psychosocial stress compromises the immune response and endochondral ossification during bone fracture healing via β-AR signaling. Proc. Natl. Acad. Sci. USA, 2019, 116: 8615-8622

[142] Heidt T, et al.. Chronic variable stress activates hematopoietic stem cells. Nat. Med., 2014, 20: 754-758

[143] Tschaffon-Müller MEA, et al.. Neutrophil-derived catecholamines mediate negative stress effects on bone. Nat. Commun., 2023, 14 3262

[144] García-Prieto J, et al.. Neutrophil stunning by metoprolol reduces infarct size. Nat. Commun., 2017, 8 14780

[145] Mittelbrunn M, Vicente-Manzanares M, Sánchez-Madrid F. Organizing polarized delivery of exosomes at synapses. Traffic, 2015, 16: 327-337

[146] Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J. Clin. Invest., 2016, 126: 1139-1143

[147] Pegtel DM, Gould SJ. Exosomes. Annu. Rev. Biochem., 2019, 88: 487-514

[148] Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells, 2017, 35: 851-858

[149] Hao Z, et al.. A multifunctional neuromodulation platform utilizing Schwann cell-derived exosomes orchestrates bone microenvironment via immunomodulation, angiogenesis and osteogenesis. Bioact. Mater., 2023, 23: 206-222

[150] Simeoli R, et al.. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat. Commun., 2017, 8 1778

[151] Meyers CA, et al.. A neurotrophic mechanism directs sensory nerve transit in cranial bone. Cell Rep., 2020, 31: 107696

[152] Cherief M, et al.. TrkA-mediated sensory innervation of injured mouse tendon supports tendon sheath progenitor cell expansion and tendon repair. Sci. Transl. Med., 2023, 15 eade4619

[153] Xu J, et al.. NGF-p75 signaling coordinates skeletal cell migration during bone repair. Sci. Adv., 2022, 8 eabl5716

[154] Williams KS, Killebrew DA, Clary GP, Seawell JA, Meeker RB. Differential regulation of macrophage phenotype by mature and pro-nerve growth factor. J. Neuroimmunol., 2015, 285: 76-93

[155] Li Y, Wang S, Xiao Y, Liu B, Pang J. Nerve growth factor enhances the therapeutic effect of mesenchymal stem cells on diabetic periodontitis. Exp. Ther. Med., 2021, 22: 1013

[156] Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther., 2013, 138: 155-175

[157] Park H, Poo M. Neurotrophin regulation of neural circuit development and function. Nat. Rev. Neurosci., 2013, 14: 7-23

[158] Kannan Y, Usami K, Okada M, Shimizu S, Matsuda H. Nerve growth factor suppresses apoptosis of murine neutrophils. Biochem. Biophys. Res. Commun., 1992, 186: 1050-1056

[159] Kannan Y, et al.. 2.5S nerve growth factor enhances survival, phagocytosis, and superoxide production of murine neutrophils. Blood, 1991, 77: 1320-1325

[160] Hepburn L, et al.. Innate immunity. A Spaetzle-like role for nerve growth factor β in vertebrate immunity to Staphylococcus aureus. Science, 2014, 346: 641-646

[161] la Sala A, Corinti S, Federici M, Saragovi HU, Girolomoni G. Ligand activation of nerve growth factor receptor TrkA protects monocytes from apoptosis. J. Leukoc. Biol., 2000, 68: 104-110

[162] Kobayashi H, Mizisin AP. Nerve growth factor and neurotrophin-3 promote chemotaxis of mouse macrophages in vitro. Neurosci. Lett., 2001, 305: 157-160

[163] Samah B, Porcheray F, Gras G. Neurotrophins modulate monocyte chemotaxis without affecting macrophage function. Clin. Exp. Immunol., 2008, 151: 476-486

[164] Susaki Y, et al.. Functional properties of murine macrophages promoted by nerve growth factor. Blood, 1996, 88: 4630-4637

[165] G. El Baassiri M, et al.. Nerve growth factor and burn wound healing: update of molecular interactions with skin cells. Burns, 2023, 49: 989-1002

[166] Villoslada P, et al.. Human nerve growth factor protects common marmosets against autoimmune encephalomyelitis by switching the balance of T helper cell type 1 and 2 cytokines within the central nervous system. J. Exp. Med., 2000, 191: 1799-1806

[167] Flügel A, et al.. Anti-inflammatory activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial migration. Eur. J. Immunol., 2001, 31: 11-22

[168] Micera A, Properzi F, Triaca V, Aloe L. Nerve growth factor antibody exacerbates neuropathological signs of experimental allergic encephalomyelitis in adult Lewis rats. J. Neuroimmunol., 2000, 104: 116-123

[169] Reinshagen M, et al.. Protective role of neurotrophins in experimental inflammation of the rat gut. Gastroenterology, 2000, 119: 368-376

[170] Prencipe G, et al.. Nerve growth factor downregulates inflammatory response in human monocytes through TrkA. J. Immunol., 2014, 192: 3345-3354

[171] Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol., 2010, 31: 24-31

[172] Liew FY, Xu D, Brint EK, O’Neill LAJ. Negative regulation of toll-like receptor-mediated immune responses. Nat. Rev. Immunol., 2005, 5: 446-458

[173] Zhao L, Lai Y, Jiao H, Huang J. Nerve growth factor receptor limits inflammation to promote remodeling and repair of osteoarthritic joints. Nat. Commun., 2024, 15 3225

[174] Farina L, et al.. Pro nerve growth factor and its receptor p75NTR activate inflammatory responses in synovial fibroblasts: a novel targetable mechanism in arthritis. Front. Immunol., 2022, 13: 818630

[175] Bandoła J, et al.. Neurotrophin receptor p75NTR regulates immune function of plasmacytoid dendritic cells. Front. Immunol., 2017, 8: 981

[176] Könnecke I, et al.. T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion. Bone, 2014, 64: 155-165

[177] Hoff P, et al.. Immunological characterization of the early human fracture hematoma. Immunol. Res., 2016, 64: 1195-1206

[178] Dar HY, et al.. Callus γδ T cells and microbe-induced intestinal Th17 cells improve fracture healing in mice. J. Clin. Invest., 2023, 133 e166577

[179] Brothers SP, Wahlestedt C. Therapeutic potential of neuropeptide Y (NPY) receptor ligands. EMBO Mol. Med., 2010, 2: 429-439

[180] Nunes AF, et al.. Neuropeptide Y expression and function during osteoblast differentiation—insights from transthyretin knockout mice. FEBS J., 2010, 277: 263-275

[181] Silva AP, et al.. Neuropeptide Y expression, localization and cellular transducing effects in HUVEC. Biol. Cell, 2005, 97: 457-467

[182] Hill EL, Elde R. Distribution of CGRP-, VIP-, D beta H-, SP-, and NPY-immunoreactive nerves in the periosteum of the rat. Cell Tissue Res., 1991, 264: 469-480

[183] Bjurholm A, Kreicbergs A, Terenius L, Goldstein M, Schultzberg M. Neuropeptide Y-, tyrosine hydroxylase- and vasoactive intestinal polypeptide-immunoreactive nerves in bone and surrounding tissues. J. Auton. Nerv. Syst., 1988, 25: 119-125

[184] Alves CJ, et al.. Bone injury and repair trigger central and peripheral NPY neuronal pathways. PLoS One, 2016, 11: e0165465

[185] Kiyota M, et al.. Periodontal tissue regeneration with cementogenesis after application of brain-derived neurotrophic factor in 3-wall inflamed intra-bony defect. J. Periodontal Res., 2024, 59: 530-541

[186] Zhang Y, et al.. Systemic injection of substance P promotes murine calvarial repair through mobilizing endogenous mesenchymal stem cells. Sci. Rep., 2018, 8 12996

[187] Hong HS, et al.. A new role of substance P as an injury-inducible messenger for mobilization of CD29⁺ stromal-like cells. Nat. Med., 2009, 15: 425-435

[188] Yeo CJ, Jaffe BM, Zinner MJ. The effects of intravenous substance P infusion on hemodynamics and regional blood flow in conscious dogs. Surgery, 1984, 95: 175-182

[189] Kim SJ, et al.. Therapeutic effects of neuropeptide substance P coupled with self-assembled peptide nanofibers on the progression of osteoarthritis in a rat model. Biomaterials, 2016, 74: 119-130

[190] Kim SJ, et al.. Self-assembled peptide-substance P hydrogels alleviate inflammation and ameliorate the cartilage regeneration in knee osteoarthritis. Biomater. Res., 2023, 27 40

[191] Wang Z, et al.. The enhancement effect of acetylcholine and pyridostigmine on bone-tendon interface healing in a murine rotator cuff model. Am. J. Sports Med., 2021, 49: 909-917

[192] Borovikova LV, et al.. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature, 2000, 405: 458-462

[193] Lee RH, Vazquez G. Evidence for a prosurvival role of alpha-7 nicotinic acetylcholine receptor in alternatively (M2)-activated macrophages. Physiol. Rep., 2013, 1: e00189

[194] Wang H, et al.. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature, 2003, 421: 384-388

[195] Olofsson PS, et al.. α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med., 2012, 18: 539-543

[196] Pavlov VA, Chavan SS, Tracey KJ. Molecular and functional neuroscience in immunity. Annu. Rev. Immunol., 2018, 36: 783-812

[197] Al-Hamed FS, et al.. Postoperative administration of the acetylcholinesterase inhibitor, donepezil, interferes with bone healing and implant osseointegration in a rat model. Biomolecules, 2020, 10: 1318

Funding

National Natural Science Foundation of China (National Science Foundation of China)(8200233)

Central Guidance on Local Science and Technology Development Fund of Zhejiang Province (No. 2024ZY01033);the Key Research and Development Program of Zhejiang (No. 2022C01076)

Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)(LY24C100001)

RIGHTS & PERMISSIONS

The Author(s)