This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.

Neuronal Control of Skin Function: The Skin as a Neuroimmunoendocrine Organ

Objectives: To identify and characterise nerve fibres and inflammatory alterations in painful Achilles tendinosis and thus gain evidence about the origin of pain in Achilles tendinosis. Methods: The composition of 10 tendon samples from patients with a prior history of painful Achilles tendinosis and 10 samples from patients with spontaneously ruptured tendons but no previous pain was compared by immunohistochemistry and conventional histology. Results: The presence of granulation tissue was shown in 8/10 cases of Achilles tendinosis. Nociceptive substance P (SP) positive nerve fibres were significantly increased, and an inflammatory infiltration comprising B and T lymphocytes was found. Additionally, small foci with iron positive haemosiderophages, indicating prior microtraumatic events, were found in 6/10 samples. None of the spontaneously ruptured tendons contained granulation tissue or haemosiderophages. Inflammatory infiltration in these patients consisted almost exclusively of granulocytes and SP positive nerve fibres were decreased. The density of sympathetic nerve fibres did not differ in the two conditions. Conclusion: Achilles tendinosis is associated with the presence of granulation tissue, haemosiderophages, and SP positive nerve fibres, which may transmit the clinically pertinent pain. Achilles tendinosis may be caused by repeated microtraumata with ensuing organisation that is accompanied by sprouting of nociceptive SP positive nerve fibres.

https://ard.bmj.com/content/annrheumdis/64/7/1083.full.pdf

Achilles tendinosis is associated with sprouting of substance P positive nerve fibres

Background:Keloids grow and spread horizontally, like malignant tumors, for reasons that remain unknown. Yet, stretching tension is clearly associated with keloid generation, as keloids tend to occur on high tension sites such as the anterior chest and scapular region. Thus, we analyzed the relation

The relationship between keloid growth pattern and stretching tension: visual analysis using the finite element method.

BackgroundThe occurrence of nerve ingrowth and its relation to chronic tendon pain (tendinopathy) are still largely unknown. In healthy tendons, the innervation is confined to the paratenon, whereas the tendon proper is devoid of nerve fibers. In this study on the pathogenesis of tendinopathy, the authors examined sensory and sympathetic nerve fiber occurrence in the patellar tendon.HypothesisNerve ingrowth and altered expression of sensory and sympathetic neuromediators play a major role in the pathophysiology of pain in patellar tendinopathy.Study DesignCase control study; Level of evidence, 3.MethodsBiopsies from the patellar tendon in patients with patellar tendinopathy (n = 10) were compared with biopsies from a control group (n = 10) without any previous or current knee symptoms compatible with patellar tendinopathy. The biopsies were stained immunohistochemically for sensory and autonomic nerve markers. The biopsies from the 2 groups were compared using subjective and semiquantitative methods.Resul...

https://journals.sagepub.com/doi/pdf/10.1177/0363546506289169

Pronociceptive and Antinociceptive Neuromediators in Patellar Tendinopathy

Keloid and hypertrophic scar: neurogenic inflammation hypotheses.

OBJECTIVE To investigate the effect of substance P (SP) on gene expression of transforming growth factor beta-1 (TGFbeta-1), transforming growth factor receptor-1 (TGFR-1) and transforming growth factor receptor-2 (TGFR-2) in fibroblasts cultured in vitro from rat's granulation tissues. METHODS The fibroblasts from the granulation tissues in the skeletal muscle of rat's hind limbs injured by formaldehyde were cultured in vitro. When different concentrations (10(-9)-10(-5) mol/L) of SP were added into the culture medium, the changes of gene expression of TGFbeta-1, TGFR-1 and TGFR-2 in the cultured fibroblasts were observed with reverse transcription polymerase chain reaction at different intervals (0, 3, 6, 12 and 24 hours after incubation). RESULTS The gene expression of TGFbeta-1, TGFR-1 and TGFR-2 in the fibroblasts cultured from rat's granulation tissues was up-regulated by SP. The peak level of the mRNA expression was found at 10(-8) mol/L SP and the up-regulation effect was not found at 10(-5) mol/L and 10(-6) mol/L. The peak levels of gene expression of TGFbeta-1, TGFR-1 and TGFR-2 in the fibroblasts treated with SP were achieved at 6 and 12 hours, respectively. CONCLUSIONS SP has up-regulation effect on the gene expression of TGFbeta-1, TGFR-1 and TGFR-2 in fibroblasts from rat's granulation tissues in vitro, and the effect is related to different stimulating concentrations of SP. It may be concerned with proliferation and differentiation of fibroblasts and formation of scar tissues during wound healing.

Effect of substance P on gene expression of transforming growth factor beta-1 and its receptors in rat's fibroblasts.

Objective To explore the relationship between substance P (SP) released from peripheral nerve endings and the expression of epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) during wound healing. Methods Fifty Wistar rats were randomly divided into 2 groups, injury group and capsaicin group. In the injury group, a full-thickness skin wound on the back of the rat was taken. The wound edge and granulation tissues were taken on the 1st, 3rd, 6th, 9th, 12th days after injury, respectively. In the capsaicin group, capsaicin was injected subcutaneously on the back of the rats to destroy the sensory nerve to prevent the secretion of SP, then a wound and sample was made in the same way. Immunohistochemistry and in situ hybridization were employed to detect the expression of SP, EGF/EGFR, and EGF mRNA/EGFR mRNA in the granulation tissues. Results In the injury group, immunohistochemical stain of SP and EGF/EGFR was located on the hair follicles and sebaceous glands at the 1st day. And the stain of SP was obvious at the 3rd day in the granulation tissues, then decreased gradually. EGF/EGFR was at low level at the 3rd day, then increased gradually and reached the peak at the 9th day, then declined. In the capsaicin group, the immunohistochemical stain of SP and EGF/EGFR was faint and without obvious change during the wound healing process. The tendency of the EGF mRNA/EGFR mRNA expression was similar to that of EGF/EGFR. Conclusions During wound healing, SP may promote the healing process by affecting the expression of EGF/EGFR in the granulation tissues.

Effect of substance P released from peripheral nerve ending on endogenous expression of epidermal growth factor and its receptor in wound healing.

Objective To study the modulating effect of sensory neuropeptide substance P (SP) on gene expression of epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2) and EGF receptor (EGFR), FGF receptor-1 (FGFR-1) in granulation fibroblast. Methods The study consisted of two parts, in vivo and in vitro. In vivo, fifty wistar rats were randomly arranged into capsaicin group and control group. The rats in capsaicin group were subcutaneously injected with neurotoxin dose of capsaicin (50 mg/kg) on the back of the rats to chemically destroy sensory nerves to prevent the release of SP. After one week, full-thickness skin wounds were created on the rats' back. SP content and EGF, EGFR, FGF-2, FGFR-1 gene expression in the granulation tissue were observed using immunohistochemistry and in situ hybridization combined with image analysis on 3rd, 6th, 9th 12th after skin injury, respectively. The experimental procedure in control group were similar with that in capsaicin group except injection with capsaicin. In vitro, SP (10(-9)-10(-5) mol/L) was added into culture medium for cultured fibroblasts from granulation and mRNA expressions of EGF, FGF-2 and their receptors were assayed with RT-PCR. Results In the present study, immunoreactive stain for SP in granulation tissue were correlated with gene expression of EGF, FGF-2 and their receptors using in situ hybridization in vivo. Once sensory nerves were destroyed and SP release was inhibited in capsaicin group, the gene expression of above growth factors and their receptors were attenuated. SP concentrations in culture medium for upregulation of mRNA expressions of EGF and EGFR in cultured fibroblasts were from 10(-8) mol/L to 10(-6) mol/L and from 10(-6) mol/L to 10(-5) mol/L, respectively. SP concentration was from 10(-9) mol/L to 10(-5) mol/L for upregulation of FGF-2 mRNA expression in cultured fibroblasts and from 10(-6) mol/L to 10(-5) mol/L for upregulation of FGFR-1. Conclusion Sensory neuropeptide SP released from sensory nerve participates in upregulation of gene expressions of EGF, EGF-2 and their receptors in granulation fibroblasts during wound healing.

[Sensory neuropeptide SP modulating expression of EGF, FGF-2 and their receptors in fibroblasts of granulation in vivo and in vitro].

OBJECTIVE To explore the role of the neuropeptide in fetal scarless wound healing. METHODS The animal models were replicated in which a full-thickness wound was inflicted on the back of rabbit fetuses at 22 days gestation (term=31 days). The progress of wound healing was observed on micro-and macro-levels at the 1 st, 2 nd, 3 rd, 5 th, 7 th, 14 th post-injury days respectively. The expression level of substance P(SP) and calcitonin gene-related peptide (CGRP) during wound healing was assessed by immunohistochemistry staining. RESULTS The cutaneous wounds in fetal rabbits healed more rapidly than that in adult and without the formation of scar. The expression of SP and CGRP of wound decreased in fetal rabbit at the early stage post-injury, down to the lowest levels on the 2 nd post-injury day (75%, 80%, vs. fetal control, both P<0.01), then increased gradually, up to the normal levels. The expression of SP and CGRP of wound decreased in adult rabbit at the early stage post-injury, down to the lowest levels on the post-injury 1 st day (60%, 76%, vs. adult control, both P<0.01), then increased quickly, up to a higher level than normal group, reaching the peak on the post-injury 7th day(168%, 126%, vs. adult control, both P<0.01), then returned to the normal levels. CONCLUSION The low level of neuropeptide may contribute to scarless wound healing in fetal rabbit.

Zheng-guo Wang

Papers

Effect of substance P on gene expression of transforming growth factor beta-1 and its receptors in rat's fibroblasts.

Effect of substance P released from peripheral nerve ending on endogenous expression of epidermal growth factor and its receptor in wound healing.

[Sensory neuropeptide SP modulating expression of EGF, FGF-2 and their receptors in fibroblasts of granulation in vivo and in vitro].

[Changes in neuropeptide substance P and calcitonin gene-related peptide in scarless wound healing in fetal rabbit skin].