The role of neuropeptides in psoriasis

The pathogenesis of psoriasis is incompletely understood but cutaneous neurogenic inflammation is probably involved. This involvement is suggested by a number of clinical and histological observations. Reports about the distribution of cutaneous nerves and the quantification of nerve growth factor and neuropeptides, including calcitonin gene-related peptide and vasoactive intestinal peptide, in lesional and nonlesional psoriatic skin suggest that sensory neuropeptides contribute to the development of psoriasis. This review summarizes what is known about the role of neurogenic markers in psoriasis.     

Ontogeny of nerves and neuropeptides in skin of rat: An immunocytochemical study

Abstract The sequence of maturation of nerves and appearance of neuropeptides was investigated in skin from fetal and neonatal rats by immunocytochemistry using antisera to protein gene product 9.5, substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY). Immunoreactivity for PGP 9.5 appeared on fetal day 16 in face and nose, somewhat later (fetal day 19) in paws and tail. The sensory neuropeptides, CGRP/substance P (fetal day 19 and postnatal day 1, respectively) appeared earlier than the autonomic peptides VIP and NPY (postnatal day 7). Thus, the study shows that neuropeptides do not appear simultaneously with nerves and that the development is rostrocaudal.     

Neuropeptides and Langerhans cells

Abstract: The immune system and nervous system are intimately related. In addition to neuroendocrine mechanisms, neuropeptides have a variety of effects on immune cells and are responsible at least in part for neurogenic inflammation. The presence of neuropeptides in the skin has been well documented. The influence of neuropeptides on Langerhans cells is the focus of this paper. The physical presence and effects of calcitonin gene-related peptide on Langerhans cells is emphasized. Discussion also includes the putative inflammatory and immunologic roles of vasoactive intestinal peptide, substance P, neurotensin, neuropeptide Y, and somatostatin in the skin.     

Some neuropeptides as modulators of experimental contact allergy

The role of some peptides in allergic contact dermatitis was investigated. The neuropeptides: substance P (SP), vasoactivc intestinal peptide (VIP) and somatostatin as well as the SP antagonist. Spantide, were injected into the same skin sites is the antigen in patients with contact allergy to nickel. The neuropeptides did not influence the eczematous reaction but spantide diminished it. This might speak for a pathogenetic role of SP in allergic, contact dermatitis.     

Evidence for neurogenic inflammation in lichen planopilaris and frontal fibrosing alopecia pathogenic mechanism

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocytic scarring alopecias affecting primarily the scalp. Although both diseases may share some clinical and histopathological features, in the last decade, FFA has become an “epidemic” particularly in Europe, North and South America with unique clinical manifestations compared to LPP, thus, raising the idea that this disease may have a different pathogenesis. Symptoms such as scalp burning, pruritus or pain are usually present in both diseases, suggesting a possible role for nerves and neuropeptides in the pathogenesis of both diseases. Based on some previous studies, neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP), have been associated with lipid metabolism and many chronic inflammatory disorders. In this study, we asked if these neuropeptides are associated with LPP and FFA scalp lesions. Alteration in the expression of SP and CGRP in affected and unaffected scalp skin from patients with both diseases was found with examination of sections using immunohistochemical techniques and confocal microscopy. We then quantitatively assessed and compared SP and CGRP expression from control, LPP and FFA scalp biopsies. Although LPP and FFA share similar histopathologic findings, opposite results were found in affected and unaffected scalp in the ELISA tests, suggesting that these diseases may have different pathogenic mechanisms. We also found presence of histopathological inflammation irrespective of evident clinical lesions, which raises the possibility that both diseases may be more generalized processes affecting the scalp.     

Neuropeptides and their receptors in psoriatic skin in relation to pruritus

BACKGROUND: Pruritus in patients with psoriasis has been reported to be more common than previously thought. OBJECTIVES: To determine the actual prevalence of pruritus in psoriasis according to severity of psoriasis and to verify the hypothesis of involvement of neuropeptides and their receptors in psoriatic pruritus. METHODS: We analysed questionnaire replies from 152 patients with chronic plaque-type psoriasis and we assayed the expression of neuropeptides and their receptors in lesional skin biopsies obtained from psoriatic patients with pruritus compared with those from psoriatic patients without pruritus, nonlesional skin of patients with pruritic psoriasis and normal controls by confocal laser scanning microscopy. RESULTS: Of the 152 patients with psoriasis, 112 (73.7%) had pruritus, and these patients had a higher mean Psoriasis Area and Severity Index (PASI) score than psoriatic patients without pruritus. There was positive correlation between the PASI score and the intensity of pruritus. Keratinocytes in the psoriatic plaques of patients with pruritus showed consistently increased expression of substance P receptor (SPR), high-affinity nerve growth factor receptor (TrkA) and calcitonin gene-related peptide receptor (CGRPR). CONCLUSIONS: Pruritus is a common feature in psoriasis. Considering the well-known roles of neuropeptides in pathogenesis of both psoriasis and pruritus, increased SPR, TrkA and CGRPR may be involved in the pathogenesis of pruritus in psoriasis and in the severity of psoriasis.     

The role of selected neuropeptides in pathogenesis of atopic dermatitis

Background Atopic dermatitis (AD) is an inflammatory skin disease of a chronic course. The role of neuropeptides in pathogenesis of this disorder is probably not crucial; however, there is evidence that these substances influence the development and course of AD. Objective The aim of this study was to evaluate the plasma level of substance P, neuropeptide Y (NPY) and calcitonin gene related peptide (CGRP) in AD patients during exacerbation and remission of the disease. Material and methods Forty‐nine patients with AD, aged 17 to 56 years, participated in the study. Among this group, there were 25 males (51%) and 24 females (49%). The disease lasted from 1 to 55 years. The severity of the disease was assessed with SCORAD index. The severity of pruritus was evaluated with Visual Analog Scale and a specially designed questionnaire. Neuropeptides plasma level was detected with radioimmunoassay. Results Substance P plasma level in AD patients during exacerbation and remission was significantly higher than in the control group. There was a negative correlation between substance P plasma level and total IgE level. CGRP plasma level during exacerbation of AD was significantly lower than in healthy controls and increased in the remission. Significantly higher CGRP concentration was observed in patients suffering from severe pruritus; however, both in patients with more and less severe pruritus, CGRP plasma level was lower than in controls. Higher CGRP plasma level was also observed in patients with more severe disease. NPY plasma level in patients with AD was significantly increased both during exacerbation and remission. During remission of AD, NPY concentration was higher than during exacerbation.     

神经肽CGRP对银屑病单核细胞趋化功能的调节

为探讨神经肽对银屑病免疫细胞的调节，及其在银屑病神经免疫发病机制中的作用，本研究利用体外细胞培养技术分离培养单核细胞，分别加入外源性神经肽降钙素基因相关肽（calcitonin gene-related peptide,CGRP)及其受体拮抗剂CGRP8－37。用ELISA检测培养单核细胞上清液中趋化因子的含量；利用微型趋化小室，观察CGRP对单核细胞趋化活性的调节。结果CGRP诱导银屑病活化的单核细胞分泌趋化因子巨噬细胞炎性蛋白－1α(macrophage inflammatory protein-1α，MIP-1α）和单核细胞趋化性蛋白－1α（monocyte chemotactic protein-1α,MCP-1α)增加，受体拮抗剂CGRP8－37则抑制这种诱导作用，同时CGRP促进单核细胞对淋巴细胞和中性粒细胞的趋化活性，用CGRP8－37后则趋化活性减弱。提示银屑病皮损内神经肽CGRP可以通过受体诱导单核巨噬细胞分泌MIP－1α和MCP－1α趋化因子，使淋巴细胞和中性料细胞在局部皮损区定向迁移与聚集，促进局部炎性细胞的浸润。     

Cutaneous vascular response to calcitonin gene-related peptide in psoriasis and normal subjects

To determine whether cutaneous blood vessels in subjects with psoriasis possess a generalized inherently abnormal response to neuropeptides, the effect of three doses of intradermally injected calcitonin gene-related peptide (CGRP) on skin blood flow in normal subjects (n= 10), and on clinically normal skin (greater than 5 cm from psoriatic lesions) in subjects with psoriasis (n= 9) was measured using a laser Doppler technique. Calcitonin gene-related peptide caused a dose-dependent increase in local blood flow in both psoriatic and normal subjects, which was not statistically different between the two groups. This study has shown that the cutaneous vasculature at sites distant from lesions of psoriasis (> 5 cm) is not inherently different from normal skin in its response to CGRP.     

Detection of the levels of neuropeptides, ACTH and cortisol in the blood of patients with polymyositis/dermatomyositis and their significance

Recent research has shown that the neuroendocrine system can regulate the function of the immune system and that ACTH and cortisol play important roles in maintaining the immune homeostasis. Polymyositis and dermatomyositis (PM/DM) are autoimmune diseases with unclear pathogeneses closely related with immune disorders, so we detected the levels of neuropeptide Y (NPY), beta-endorphin (beta-EP), calcitonin gene-related peptide (CGRP), adrenocoricotropic hormone (ACTH), and cortisol in blood of patients with PM/DM to investigate the relationship between these indices and the pathogenesis of PM/DM. The detection of NPY, beta-EP, CGRP, and ACTH concentrations in plasma and cortisol in serum of 28 cases of PM/DM was carried out using radioimmunoassay methods, and the results were compared with those of 20 normal controls. The levels of NPY in the plasma of PM/DM was significantly higher than those of the controls, while beta-EP, CGRP and ACTH were significantly lower than those of the controls, and cortisol was not significantly different before treatment. Linear correlation analysis indicated that NPY was significantly positively correlated with CPK, and beta-EP and CGRP were significantly negatively correlated with CPK. There were no significant correlations among cortisol ACTH, and CPK and no significant correlations between NPY, beta-EP, CGRP, ACTH, cortisol and age or duration of disease before treatment. After treatment for three months, NPY, beta-EP and CGRP tended to become normal and no longer significantly different from the control values. However, ACTH fell further and was significantly lower than the level before treatment. Therefore the increase in NPY and the decreases in beta-EP, CGRP, and ACTH in the plasma of PM/DM patients may be related to the pathogenesis of PM/DM.     

Calcitonin gene-related peptide modulates interleukin-13 in circulating cutaneous lymphocyte-associated antigen-positive T cells in patients with atopic dermatitis

Background  Neuropeptides (NPs) may play an important role in the pathogenesis of atopic dermatitis (AD) by regulating immune responses and contributing to the cross-talk between the immune and nervous systems.
Objectives  To assess the ability of NPs to influence interleukin (IL)-13 and interferon (IFN)-γ production and the expression of the activation marker HLA-DR in skin memory T cells [cutaneous lymphocyte-associated antigen (CLA)+ T cells] from patients with AD with severe, chronic lesions and intense pruritus, and from nonatopic controls.
Methods  Cells were cultured in the presence and absence of different NPs, calcitonin gene-related peptide (CGRP), somatostatin (SOM) and substance P (SP). IL-13 and IFN-γ production and HLA-DR expression were measured in both CLA+ and CLA− T-cell subsets by flow cytometry.
Results  CGRP increased IL-13 production in peripheral blood mononuclear cells from patients with AD ( P  <   0·05), with no changes detected in the presence of SOM or SP. These patients with AD had a lower expression of CGRP receptor compared with controls ( P  <   0·05). Memory T cells incubated with CGRP also showed an increase in IL-13 ( P  <   0·05) and HLA-DR ( P  <   0·05) in CLA+ T cells from patients with AD compared with controls, but not in CLA− T cells. Patients with a higher production of IL-13 were those with higher total IgE and percentage of skin area involved. Furthermore, the IL-13/IFN-γ ratio was increased in patients with AD after cells were cultured with CGRP ( P  <   0·05).
Conclusions  Our results suggest an immunomodulatory role of CGRP towards a Th2 pattern in CLA+ T cells, which may contribute to exacerbating clinical symptoms in patients with AD.     

斑秃患者血浆和皮损中降钙素基因相关肽、血管活性肠肽的研究

目的 探讨降钙素基因相关肽(CGRP)和血管活性肠肽(VIP)在斑秃发病中的作用。方法 利用放射免疫分析法检测30例斑秃患者和20例正常人血浆中的CGRP和VIP水平,利用免疫组化方法检测21例斑秃患者皮损和16例正常人头皮中的CGRP和VIP表达情况。结果 ①斑秃活动期患者血浆中的CGRP水平为(142.63±67.95)pg/mL,低于稳定期(197.33±67.15)pg/mL和正常人(188.40±72.95)pg/mL,差异均有显著性。②斑秃活动期血浆中的VIP水平为(105.94±55.42)pg/mL,低于斑秃稳定期(156.86±47.37)pg/mL和正常人(176.44±84.70)pg/mL,差异均有显著性。③CGRP和VIP在斑秃皮损及其周围的表达明显低于正常人,差异有显著性。结论 CGRP和VIP在斑秃发病中起一定的作用。     

Dialog between skin and its microbiota: Emergence of “Cutaneous Bacterial Endocrinology”

Microbial endocrinology is studying the response of microorganisms to hormones and neurohormones and the microbiota production of hormones-like molecules. Until now, it was mainly applied to the gut and revealed that the intestinal microbiota should be considered as a real organ in constant and bilateral interactions with the whole human body. The skin harbours the second most abundant microbiome and contains an abundance of nerve terminals and capillaries, which in addition to keratinocytes, fibroblasts, melanocytes, dendritic cells and endothelial cells, release a huge diversity of hormones and neurohormones. In the present review, we will examine recent experimental data showing that, in skin, molecules such as substance P, calcitonin gene-related peptide, natriuretic peptides and catecholamines can directly affect the physiology and virulence of common skin-associated bacteria. Conversely, bacteria are able to synthesize and release compounds including histamine, glutamate and γ-aminobutyric acid or peptides showing partial homology with neurohormones such as α-melanocyte-stimulating hormone (αMSH). The more surprising is that some viruses can also encode neurohormones mimicking proteins. Taken together, these elements demonstrate that there is also a cutaneous microbial endocrinology and this emerging concept will certainly have important consequences in dermatology.     

Neuronal changes in psoriasis exacerbation

Background The nervous system contributes to inflammatory skin diseases.
Objective The aim of this investigation was to study the neuronal contribution to psoriasis at the remission and exacerbation phases.
Methods We examined the expression of the neuronal markers protein gene product 9.5 (PGP 9.5), growth-associated protein-43 (GAP-43) and substance P, in addition to its receptor (R), neurokinin-1R (NK-1R) in psoriatic skin from seven female patients at remission and exacerbation, using immunohistochemistry.
Results The number of epidermal PGP 9.5 immunoreactive nerve fibres in the involved skin during exacerbation was decreased ( P  < 0.01) compared to involved skin at remission and non-involved skin at the exacerbation phase. GAP-43-positive nerve fibres were decreased ( P  < 0.05) in the involved skin in contrast to non-involved skin, during exacerbation. Substance P expression was seen on both immunoreactive nerve fibres and cells with a down-regulation ( P  < 0.01) in the number of positive nerve fibres in the involved skin compared to non-involved skin, at the exacerbation phase. The number of substance P-positive cells was slightly lower in the involved skin at exacerbation than at remission. The number of NK-1R immunoreactive cells was increased ( P  < 0.01) in the involved skin in contrast to non-involved skin, at the exacerbation phase.
Conclusion Our findings suggest a crosstalk between the nervous system and inflammation during psoriasis exacerbation in the form of an altered expression of nerve fibres, substance P and its NK-1R.     

仙方消银片对寻常型银屑病患者血浆内皮素1及降钙素基因相关肽含量的影响

目的 :　研究仙方消银片对寻常型银屑病患者血浆内皮素 1(ET - 1)及降钙素基因相关肽(CGRP)含量的影响 ,为该方疗效提供科学依据。方法 :　采用放射免疫法分析 5 0例银屑病患者ET - 1和CGRP的含量变化。结果 :　仙方消银片能拮抗血浆中过高的内皮素水平 (P <0 .0 1) ,可以明显提高血浆中过低的CGRP的浓度 (P <0 .0 5 )。结论 :　仙方消银片有助于抑制细胞增殖和新血管形成 ,对于调节皮肤的免疫应答反应有重要意义     

Prurigo nodularis: a review

Prurigo nodularis is a chronic condition characterized by a papulonodular pruriginous eruption of unknown aetiology. This condition is a difficult disease to treat and causes frustration to both the patient and the treating doctor. A variety of systemic conditions have been reported to be associated with prurigo nodularis. The mechanism by which these disorders may trigger prurigo nodularis is unknown. Nerve growth factor has been implicated in the pathogenesis of prurigo nodularis. Calcitonin gene-related peptide and substance P immunoreactive nerves are markedly increased in prurigo nodularis when compared with normal skin. These neuropeptides may mediate the cutaneous neurogenic inflammation and pruritus in prurigo nodularis. Topical or intralesional glucocorticoids are the treatment of choice. Other topical treatments such as topical vitamin D3, and topical capsaicin have also been reported to be effective. Oral treatments such as cyclosporin and thalidomide have been shown to improve both appearance of the skin and pruritus. We review the clinical features, associations, pathology, pathogenesis and treatment of prurigo nodularis.     

Plasma homocysteine and folate levels in patients with chronic plaque psoriasis

Background Hyperhomocysteinaemia is a well‐known risk factor for cardiovascular diseases. Patients with severe chronic plaque psoriasis have a higher risk of death due to arterial and/or venous thrombosis. Objectives To investigate the relationship among plasma homocysteine and folate levels and severity of chronic plaque psoriasis in a selected cohort of patients with psoriasis without known risk factors for acquired hyperhomocysteinaemia. Methods We performed a case–control study in 40 patients with chronic plaque psoriasis and 30 age‐ and sex‐matched healthy controls. Cases and controls were selected excluding individuals with conditions or diseases associated with acquired hyperhomocysteinaemia, and were also asked to stop alcohol and coffee consumption for 1 week before blood sampling. The plasma levels of homocysteine and folic acid were measured and were correlated with the severity of psoriasis (Psoriasis Area and Severity Index, PASI). Results Patients with psoriasis had plasma homocysteine levels higher than controls (mean ± SD 16·0 ± 5·6 vs. 10·4 ± 4·7 μmol L^?1; P < 0·001). Conversely, folic acid levels were lower in patients with psoriasis compared with controls (mean ± SD 3·6 ± 1·7 vs. 6·5 ± 1·7 nmol L^?1; P < 0·001). Plasma homocysteine levels in patients with psoriasis correlated directly with disease severity (PASI) and inversely with folic acid levels. Plasma folic acid levels were inversely correlated with the PASI. No abnormalities of plasma vitamin B₆ and B₁₂ were found. Conclusions Patients with psoriasis may have a tendency to hyperhomocysteinaemia, which may predispose to higher cardiovascular risk. Dietary modification of this risk factor appears relevant to the global management of patients with moderate to severe psoriasis.     

银屑病患者血清食物变应原特异性IgE、IgG的检测

目的 探讨银屑病患者食物变应原特异性IgE、IgG的检测结果。方法 对102例银屑病患者进行了食物变应原特异性IgE、IgG检测,同时对慢性湿疹患者、慢性荨麻疹患者、健康体检者进行检测。结果银屑病、慢性湿疹、慢性荨麻疹患者3组间食物特异性IgE、食物特异性IgG检测的阳性例数比较,差异均无统计学意义。银屑病、慢性湿疹、慢性荨麻疹患者分别与健康体检组的阳性例数比较,差异均有统计学意义。结论 食物变应原与银屑病的致病有关,银屑病与慢性湿疹、慢性荨麻疹患者变应原来源和种类不一,值得进一步研究。     

Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems

Abstract: The interaction between components of the nervous system and multiple target cells in the cutaneous immune system has been receiving increasing attention. It has been observed that certain skin diseases such as psoriasis and atopic dermatitis have a neurogenic component. Neuropeptides released by sensory nerves that innervate the skin and often contact epidermal and dermal cells can directly modulate functions of keratinocytes, Langerhans cells (LC), mast cells, dermal microvascular endothelial cells and infiltrating immune cells. Among these neuropeptides the tachykinins substance P (SP) and neurokinin A (NKA), calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and somato statin (SOM) have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production or antigen presentation under physiological or pathophysiological conditions. Expression and regulation of their corresponding receptors that are expressed on a variety of skin cells as well as the presence of neuropeptidespecific peptidases such as neutral endopeptidase (NEP) or angiotensinconverting enzyme (ACE) determine the final biological response mediated by these peptides on the target cell or tissue. Likewise, skin cells like keratinocytes or fibroblasts are a source for neurotrophins such as nerve growth factor that are required not only for survival and regeneration of sensory neurons but also to control responsiveness of these neurons to external stimuli. Therefore, neuropeptides, neuropeptide receptors, neuropeptidedegrading enzymes and neurotrophins participate in a complex, interdependent network of mediators that modulate skin inflammation, wound healing and the skin immune system. This review will focus on recent studies demonstrating the role of tachykinins, CGRP, SOM and VIP and their receptors and neuropeptide-degrading enzymes in mediating neurogenic inflammation in the skin.