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. Author manuscript; available in PMC: 2021 Jan 1.
Published in final edited form as: Auton Neurosci. 2019 Nov 26;223:102610. doi: 10.1016/j.autneu.2019.102610

Autonomic nerve dysfunction and impaired diabetic wound healing; the role of neuropeptides

Georgios Theocharidis 1, Aristidis Veves 1
PMCID: PMC6957730  NIHMSID: NIHMS1545219  PMID: 31790954

Abstract

Lower extremity ulcerations represent a major complication in diabetes mellitus and involve multiple physiological factors that lead to impairment of wound healing. Neuropeptides are neuromodulators implicated in various processes including diabetic wound healing. Diabetes causes autonomic and small sensory nerve fibers neuropathy as well as inflammatory dysregulation, which manifest with decreased neuropeptide expression and a disproportion in pro- and anti- inflammatory cytokine response. Therefore to fully understand the contribution of autonomic nerve dysfunction in diabetic wound healing it is crucial to explore the implication of neuropeptides. Here, we will discuss recent studies elucidating the role of specific neuropeptides in wound healing.

Introduction

The skin is densely innervated by an interconnected system of highly specialized afferent sensory and efferent autonomic nerve fibers (1, 2). Cutaneous autonomic nerve fibers almost completely derive from sympathetic neurons and albeit very effective, they represent only a minority of skin nerve fibers in comparison with sensory nerves. In addition, as opposed to sensory nerves, the distribution of autonomic nerve fibers is restricted to the dermis, innervating blood vessels, lymphatic vessels, erector pili muscles, apocrine and eccrine glands, and hair follicles. Therefore, cutaneous autonomic nerve fibers take part in the modulation of blood circulation, lymphatic function, and skin appendages regulation (3). Diabetic patients’ skin exhibits motor, sensory and autonomic fiber denervation: sensory neuropathy restricts the sensations of pain, temperature, pressure and others; autonomic denervation leads to arteriovenous shunting, thereby causing vasodilation in small arteries; motor neuropathy induces weakness and wasting of small intrinsic muscles (4). Importantly, microcirculation is affected in the diabetic neuropathic foot, mainly through impairment of both endothelium dependent and independent vasodilation (5) and peripheral blood flow is elevated and associated with arteriovenous shunting (6, 7). Finally, another consequence of autonomic denervation is sudomotor dysfunction that leads to dry skin and callus formation that play an important role in the development of diabetic foot ulceration

A growing body of studies in both patients and animal models points to a synergistic role of cutaneous nerve fibers and the immune system in mediating wound healing. The regulation of the healing response is realized through intricate interplay of components of the local immune and nervous system, which is further regulated via endocrine feedback (8-10). Neuropeptides are neuronal short-chain polypeptides that act as signaling molecules affecting numerous processes. Cutaneous nerve fibers and inflammatory cells such as monocytes, macrophages and eosinophils are known to release neuromodulators including cytokines and neuropeptides that regulate the activity of specific cytokine and neuropeptide receptors on a variety of skin cells including mature T and B cells, Langerhans cells, endothelial cells, mast cells, fibroblasts and keratinocytes resulting to the direct activation of G-protein signaling cascades (1, 11). Figure 1 summarizes how diabetes and neuropeptide expression dysregulation culminate in aberrant wound healing. Neuropeptide Y (NPY), Substance P (SP) and calcitonin gene related peptide (CRGP) are neuropeptides involved in modulating the immune response and wound healing. Further, other neuropeptides such as Melanocyte Stimulating Hormone (MSH) and Neurotensin are also neuromodulators and could potentially participate in impaired diabetic wound healing. These neuropeptides are released from autonomic nerve fibers as well as from cells within the dermis and the epidermis (8). Furthermore, these neuropeptides regulate the expression and function of numerous cytokines that are implicated and dysregulated in diabetes including IL-1, IL-6, IL-8, IL-10 and TNF-α (9).

Figure 1. Diabetic neuropathy and neuropeptide dysregulation contribute to lower extremity wound pathogenesis.

Figure 1

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Diabetes mellitus causes autonomic and small sensory nerve fibers neuropathy in the lower extremity as well as inflammatory dysregulation, which manifest with reduced neuropeptide expression and disproportion in pro- and anti- inflammatory cytokine response. Neuropeptides have a direct effect on leukocytes and further contribute to the cytokine imbalance. Also, cytokines and neuropeptides directly influence various skin cells including fibroblasts, keratinocytes and endothelial cells decreasing their proliferation and resulting in irregular angiogenesis, ECM production and reepithelialization. Reduced neovascularization, reepithelialization and dysregulation in remodeling and granulation tissue deposition, also affected by the abnormal cytokine expression profile, lead to impaired cutaneous wound healing. Adapted from (9).

Neuropeptide Y (NPY)

NPY is a highly conserved 36 amino acid polypeptide involved in dysregulated healing, and is one of the most abundant neurotransmitters in the mammalian central (CNS) and peripheral nervous system (PNS) (9). Besides the nerves, other non-neuronal cells have been reported to produce NPY, including megakaryocytes, liver, spleen, and ECs (12, 13). NPY is mostly studied for its impact on the central nervous system, where it induces conservation of energy and counteracts the effects of Leptin. Thus, most of the NPY diabetes studies focus on its CNS effects (9). In the hypothalamus of both type 1 and type 2 diabetic patients, NPY expression is elevated while in the skin, it is decreased (14-16). In a recent study NPY in the plasma of type 2 diabetic patients was found to be increased; however there is no data on dermal NPY expression for these patients. Baseline expression of NPY remains unchanged in a diabetic rabbit model of cutaneous wound healing (17). In addition, NPY has a pro-angiogenic effect and regulates elements of the innate and adaptive immune system (9). Specifically, NPY modulates cell migration, cytokine release from macrophages and helper T cells, antigen presentation as well as activation of natural killer cells and antibody production (18-20). Platelet lysate derived NPY was recently shown to affect migration and angiogenesis potential of human adipose derived stromal cells and co-localized with endothelial markers CD31 and VEGF in difficult to heal wound samples treated with lysate (21). NPY is mostly known to be associated with tendon and cartilage healing, but through its pro-angiogenic receptors NPY-2R and NPY-5R it also influences cutaneous healing (22-25). Notably, in genetically modified mice where NPY-2R was deleted, a significant delay in cutaneous wound healing with decreased neovascularization was reported (26). The enzyme dipeptidyl peptidase IV (DPP IV) that cleaves NPY into its pro-angiogenic form, which subsequently binds to NPY-2R and NPY-5R receptors, is enriched in aging mice (27, 28). NPY is thus involved in both the inflammatory and angiogenic phases of wound healing. More research is necessary to elucidate the exact role of NPY in diabetic wound healing.

Substance P (SP)

A member of the tachykinin neuropeptide family, SP is an 11 amino acid neuropeptide encoded by the TAC1 gene and is one of the main neuropeptides released by C-nociceptive fibers in response to injury (29). In the last two decades, SP has emerged as a potent modulator of cutaneous wound healing among all healing associated neuropeptides. The pro-angiogenic function of SP has been demonstrated in both in vitro and in vivo experiments and importantly SP has been reported to have a critical role in wound site infiltration of polymorphonuclear leukocytes (30, 31). SP also promotes proliferation in fibroblasts (32) and inhibits apoptosis through increasing the levels of BCL-2 and proliferating cell nuclear antigen in burn wounds (33). Noteworthy, SP has been found to be decreased in skin biopsies from both type 1 and type 2 diabetic patients (34) and SP mRNA and protein expression is diminished in a rabbit model of type 1 diabetes (17). Exogenous treatment of diabetic wounds with SP resulted in faster healing in both mice and rats (31, 35-37). In addition, topical administration of SP on excisional wounds in a db/db mouse model led to increased leukocyte infiltration compared to saline treatment at the early stages post-wounding, suggesting a role for SP involvement during early inflammation in wound healing (38). Moreover, the enzyme that inactivates SP, neutral endopeptidase (NEP) or neprilysin, is increased in diabetes and the use of a NEP inhibitor has been effective in accelerating diabetic wound healing (39). In a rabbit model of diabetic wound-healing, our group has demonstrated reduced SP levels in the diabetic rabbit skin compared to non-diabetic and post-wounding, both NPY and SP gene expression is diminished regardless of diabetic status (17). In endothelial cells, SP is an established vasodilating factor by inducing the production of nitric oxide, consequently enhancing endothelial permeability and leukocyte extravasation into the underlying tissues (40). It has been recently reported to promote the mobilization of endothelial progenitor cells in the wounded tissue of a murine model of type 2 diabetes and increase the amount of Yes-associated protein expression in the dermis (36). Furthermore, it acts as a potent chemoattractant for immune cells, promotes elevated expression of endothelial leukocyte adhesion molecule-1 on human microvascular endothelial cells and leukocyte function-associated antigen-1 (LFA-1) on murine endothelial cells and lymphocytes and can raise the levels of an array of inflammation linked cytokines including TGF-beta, TNF-α, IL-1β, IL-2, IL-8, IL-6 from dendritic and T cells, neutrophils, macrophages and fibroblasts (41-53). Hence by generating a pro-inflammatory environment within the wound site SP plays a crucial role in the inflammatory and angiogenic phases of wound healing.

Calcitonin Gene Related Peptide (CGRP)

CGRP is a 37 amino acid neuropeptide produced by an alternative splicing of the calcitonin gene (54). Just like NPY, CGRP is present in both the CNS and the PNS. In the PNS, CGRP is stored and released together with SP from capsaicin sensitive peripheral afferent neurons and is also a potent vasodilator (55-57). Notably, co-application of CGRP and SP to human skin induced long lasting vasodilation in a dose-dependent manner highlighting a synergistic effect of the two neuropeptides (58). Comparable to NPY, CGRP is found to be expressed outside the neurons in diverse organs such as the kidneys, liver, lungs and prostate (59). In peripheral tissues, CGRP receptors exist in the heart, liver, spleen, skeletal muscle, lungs, lymphocytes and the vasculature (55). A marked reduction of CGRP reactive fibers has been reported in the dermis of type 1 and type 2 diabetic patients (34). Diabetes has been shown to decrease the levels of CGRP in murine hearts, limit CGRP-mediated vasodilation in rats and diminish both CGRP and CGRP receptor expression in a rat model of diabetic cardiomyopathy (60-67). CGRP is also involved in the wound healing process by promoting neovascularization through elevated VEGF secretion from wound site cells and triggering the cAMP pathway (68, 69). Moreover, CGRP induces release of both IL-1α and IL-8 in keratinocytes, IL-8 in the corneal epithelium, IL-1α, IL-8 and ICAM-1 in airway epithelium, IL-1β and TNF-α in macrophages, IL-1β, IL-6 and TNF-α in dental pulp fibroblasts, and acts as a chemoattractant for T cells, mediates lymphocyte proliferation and inhibits IL-2 expression (70-76). In animal models of diabetes CGRP was also decreased in tissues such as the heart and the dorsal root ganglion, but not much is known about its cutaneous expression (62-64). In a recent study, vacuum-assisted treated wounds in a diabetic mouse model exhibited a significant increase in dermal and epidermal nerve fiber densities and in SP, CGRP, and nerve growth factor expression. In particular, the cyclical treatment mode correlated with the largest enhancement in granulation tissue production, and a slightly quicker wound closure rate (77). In CGRP-null mice (CGRP−/−), neovascularization and wound healing were impaired in comparison with control wild-type mice, and a reduction in the levels of VEGF from the wound granulation tissue was demonstrated (78). These findings indicate that the association of CGRP in wound healing is modulated through its impact on angiogenesis. Thus, exogenous CGRP addition may promote enhanced angiogenesis and wound healing.

Neurotensin (NT)

The 13 amino acid neuropeptide NT is primarily produced in the CNS (mainly hypothalamus, amygdala and nucleus accumbens) and in endocrine cells (N cells) of the ileum and jejunum. NT inhibits CNS dopaminergic pathways and promotes growth of various gastrointestinal tissues as well as adrenal gland, hepatocytes and fibroblasts (79). The NT receptors neurotensin receptor 1, neurotensin receptor 2 and sortilin, are found throughout the CNS (80). According to different studies, NT may be involved in the pathogenesis of diabetes. Increased levels and total amounts of NT are found in the pancreas of obese (ob/ob) mice and in the intestine of both ob/ob and diabetic (db/db) mice (81). Similarly, insulin mediates NT concentrations in the pancreas, with high NT levels correlating with insulin deficiency in ob/ob and db/db mice (82). Nevertheless, in another study, NT expression was comparable between lean and diabetic mice. In addition, research in human patients did not reveal any difference in NT amounts between healthy nondiabetic subjects and lean and obese diabetic patients either pre- or postprandially (83, 84). NT has been reported to affect wound healing by modulating cell functions of both innate and adaptive immunity, namely macrophages and T cells (85-89). NT expressing nerve fibers and NT mRNA are both present in the skin. Cutaneous NT activates skin mast cells causing secretion of histamine (90, 91). In a recent study, in vitro treatment of keratinocytes and T cells with NT was shown to enhance migration and reduced the expression of TNF-α and IL-8. Interestingly, co-stimulation with SP led to decreased migratory capacity, while the angiogenesis in HUVEC cells was elevated (92). NT also has an effect on cutaneous dendritic cells through downregulation of activation of inflammatory pathways JNK and NF-κB and reduction of expression of inflammatory cytokines IL-6, TNF-α and IL-10 (93). Noteworthy, in two different mouse diabetic wound healing studies, delivery of NT with specially designed biomaterials enhanced wound closure. Collagen dressings functionalized with NT reduced inflammation and accelerated wound healing (94), whereas PLGA membranes loaded with NT also resulted in more rapid wound healing and decrease in inflammatory cytokine expression (95). Therefore, topical delivery of NT could potentially be a promising treatment for diabetic foot ulcers.

alpha-Melanocyte-stimulating hormone (a-MSH)

a-MSH is a 13 amino acid hormone and neuropeptide and belongs to the family of melanocortins, a number of structurally related peptides that not only participate in the regulation of pigmentation and cortisol expression but also modulate food intake, energy homeostasis, exocrine gland function, and inflammatory response (96). a-MSH is a proteolytic cleavage product of proopiomelanocortin (POMC) and is predominantly released from the pars intermedia region of the pituitary gland. (97). Noteworthy, significant amounts of a-MSH are present in the human skin (98-100). A number of different cutaneous cell types including keratinocytes, fibroblasts, melanocytes and endothelial cells generate a-MSH and express melanocortin receptors (MCRs). Long-term activation of a-MSH decreases body weight and improves glucose metabolism in a model of diet-induced obesity (101). Two diabetic rat studies demonstrated that POMC mRNA in arcuate nucleus, pituitary and the hypothalamus is diminished and cannot be reversed following insulin treatment (102) (103). What is more, a-MSH has been reported to have anti-inflammatory effects and has been known to block inflammatory pathways (104-109). In human dermal fibroblasts α-MSH regulates the expression of IL-8 (110), while in human peripheral blood monocytes and cultured monocytes, α-MSH enhances the expression of the anti-inflammatory cytokine IL-10. In septic patients, small concentrations of α-MSH added to LPS-stimulated whole blood samples inhibit TNF-α and IL-1β production and in RAW264.7 mouse macrophages cell line a-MSH inhibits nitric oxide generation induced by LPS and IFN-γ treatment (111-115). Moreover, a-MSH suppresses the expression CD86, a major T cell costimulatory molecule, in activated monocytes and M1 classically activated macrophages and promotes the expression of the anti-inflammatory cytokine IL-10 in human peripheral blood monocytes and cultured human monocytes (116). In endothelial cells, α-MSH causes an increase in the release of IL-8, while in stimulated dermal fibroblasts it reduces IL-8 release and in human keratinocytes increases production of IL-10 (110, 117-119). In murine cutaneous wound healing as well as human burn wounds and hypertrophic scars upregulation of both a-MSH and its receptor was observed. Cells positive for a-MSH were epidermal keratinocytes, fibroblasts and inflammatory cells (120). In a rabbit model of corneal wound healing, topical delivery of the C-terminal tripeptide sequence of a-MSH (a-MSH11–13) ameliorated the healing response (121). Furthermore, intraperitoneal injection of a-MSH prior to injury led to significant reduction of leukocytes and mast cells in the granulation tissue of mice 3 and 7 days post-wounding and reduced scar area and collagen fiber organization on day 40 after injury (122). Hence, it appears that a-MSH influences inflammatory pathways and its presence in the skin and involvement in various functions of different skin cell types makes it an attractive target for additional cutaneous diabetic wound healing studies (123).

A number of other neuropeptides have also been lately implicated in cutaneous wound healing. Somatostatin was shown to exert an inhibitory effect on keratinocyte migration and proliferation both in vitro and on an ex vivo porcine wound healing model (124). Adrenomedullin topically delivered in a sustained-release ointment formation significantly improved wound closure in pressure ulcer patients through acceleration of granulation tissue formation and enhanced neovascularization (125). In addition, when used in a combination treatment with its binding protein adrenomedullin also promoted faster wound repair in a rat model of cutaneous healing (126). Endothelial cell-specific endothelin-1 knockout mice exhibited faster wound healing rates and attenuated fibrosis (127) and the role of endothelin-1 in promoting fibrosis is well documented (128). Using topical gene therapy with the angiogenic neuropeptide secretoneurin in mice resulted in accelerated diabetic wound healing with elevated arteriole and capillary densities in the wounded area (129). Lastly, treatment of diabetic mice with the neuropeptide relaxin at the wound site lead to increased angiogenesis, vegf mRNA expression and elevated MMP11 levels (130).

Summary

The functions of diverse neuropeptides have been studied in detail in the brain, but remain underexplored in other densely innervated organs, like the skin. The above studies clearly suggest that the cutaneous nervous system is not only responsible for sensory neurotransmissions to the CNS but plays a crucial role in various skin functions including wound healing. Importantly, they have been associated with impaired diabetic wound healing. More comprehensive investigations of the function of each neuropeptide may assist in determining which neuropeptide is more important in the skin, both in physiological and pathological conditions, and to what extent. Finally, with various positive studies in animal models of wound healing, utilizing neuropeptides for therapeutic interventions of the diabetic foot ulceration could be a promising strategy.

Acknowledgments

Funding

This work was supported by the National Institutes of Health Grant DP3DK108224 (AV). AV received funding from the National Rongxiang Xu Foundation. GT received a George and Marie Vergottis Foundation Postdoctoral Fellowship award.

Footnotes

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