Clinical, cellular, and molecular aspects in the pathophysiology of rosacea

Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a "developmental march" of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating "human disease model" for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology.     

玫瑰痤疮神经源性炎症及肉毒毒素治疗相关机制的研究进展

【摘要】 局部血管神经功能失调是玫瑰痤疮发病的重要因素,已证实神经源性炎症是神经血管失调的重要环节,而皮内注射肉毒毒素可缓解面部潮红、灼热表现,可能与抑制神经末梢神经肽释放以及抑制肥大细胞脱颗粒有关。本文综述玫瑰痤疮发病机制中神经源性炎症以及肉毒毒素治疗玫瑰痤疮的相关研究进展,以期为玫瑰痤疮神经相关基础研究及临床治疗提供依据。     

Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.     

Aktuelles Verständnis der Pathophysiologie der Rosazea

Rosacea is a chronic inflammatory skin disease mainly affecting the face. Four major clinical subtypes of rosacea can be identified: erythemato-telangiectatic, papulopustular, phymatous and ocular rosacea. Still, it is currently unclear whether these subtypes develop consecutively or if any subtypes may occur individually as part of a syndrome. Rosacea is characterized by facial flushing, erythema, chronic inflammation, edema and fibrosis. Several trigger factors can worsen the disease or cause recurring episodes of inflammation. Although some aspects in the pathophysiology of rosacea have been characterized in more detail during the past years, the precise interplay of the various dysregulated systems is still poorly understood. In early disease manifestations and milder stages, dysfunction of neurovascular regulation and the innate immune system seem to be driving forces in rosacea pathophysiology. A disturbed chemokine and cytokine network further contributes to disease progression. This current review highlights some of the recent findings in rosacea pathophysiology and points out novel targets for therapeutic intervention.     

Integrative concepts of rosacea pathophysiology,clinical presentation and new therapeutics

Rosacea is a chronic relapsing inflammatory skin disease with high prevalence worldwide. Recent research suggests that dysregulation of innate and adaptive immune pathways as well as neurovascular changes is present, with different degrees of importance in the various subtypes. Neither the aetiology, genetics nor pathophysiological basis of the vascular, inflammatory or fibrotic changes is well understood. The clinical spectrum comprises a huge variability from erythema (vasodilation) to papules/pustules (inflammatory infiltrate) to phymata (fibrosis, glandular hyperplasia) making it a valuable human disease model to understand the interplay between the neurovascular and immune systems as well as the progression from chronic inflammation to fibrosis in skin. The lack of appropriate animal models emphasizes the importance of further translational research validating observed molecular pathways under disease conditions. A wide spectrum of physical (UV, temperature), biological (microbiota, food) and endogenous (genetic, stress) stimuli has been discussed as “trigger factors” of rosacea. Novel findings implicate keratinocytes, smooth muscle cells, endothelial cells, macrophages, mast cells, fibroblasts, Th1/Th17 cells, antibody‐producing B cells and neurons in the pathobiology of rosacea. So far, pattern recognition receptors like TLR2, transient receptor potential ion channels, cytokines, chemokines and proteases have been implicated as critical receptors/mediators. However, our understanding of the interactive networks on the molecular level is very limited. Identification of critical molecular components of the inflammatory cascade including antimicrobial peptides, the IL‐1β inflammasome, TNF, IFN‐γ, proteases and neuropeptides may provide the basis for novel pathomechanism‐based therapeutic approaches for this frequent and bothersome skin disease.     

Role of neuroimmune circuits and pruritus in psoriasis

Psoriasis is a chronic inflammatory skin disease presenting with an array of clinical phenotypes, often associated with pruritus. Environmental and psychological stressors can exacerbate psoriasis symptoms and provoke flares. Recent studies suggest a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis in some patients with psoriasis that can result in immune dysregulation. The immune system, in turn, can communicate with the nervous system to induce, maintain or aggravate psoriasis. In the skin, peripheral sensory as well as autonomic nerves control release of inflammatory mediators from dendritic cells, mast cells, T cells or keratinocytes, thereby modulating inflammatory responses and, in case of sensory nerves, pruritus. In response to the environment or stress, cytokines, chemokines, proteases, and neuropeptides fluctuate in psoriasis and influence immune responses as well as nerve activity. Furthermore, immune cells communicate with sensory nerves which control release of cytokines, such as IL-23, that are ultimately involved in psoriasis pathogenesis. Nerves also communicate with keratinocytes to induce epidermal proliferation. Notably, in contrast to recent years the debilitating problem of pruritus in psoriasis has been increasingly appreciated. Thus, investigating neuroimmune communication in psoriasis will not only expand our knowledge about the impact of sensory nerves in inflammation and pruritus and give new insights into the impact of environmental factors activating neuroimmune circuits or of stress in psoriasis, but may also lead to novel therapies. This review summarizes the relevant literature on the role of neuroimmune circuits, stress and how the central HPA axis and its peripheral equivalent in the skin, impact psoriasis.     

Quantitative analysis of contact sites between mast cells and sensory nerves in cutaneous psoriasis and lichen planus based on a histochemical double staining technique

Summary The aim of the present study was to test further our previous hypothesis that the inflammatory reaction in psoriasis is neurogenic. For this purpose, contact sites between mast cells and sensory nerves were morphometrically analysed in the basement membrane zone, papillary dermis and three dermal zones of lesional/non-lesional psoriatic and lichen planus skin as well as in healthy control skin. The analyses were made on sections stained with a histochemical double stain developed for this study. With the double stain, active mast cell tryptase was stained blue enzyme histochemically, and the sensory nerves black using specific monoclonal anti-neurofilament antibodies with immunogold. In psoriatic lesions, both mast cells and mast cell — nerve contacts were markedly more frequent in the basement membrane zone and in the papillary dermis when compared with the corresponding areas in the other groups. Mast cell numbers were increased in both lesional and symptom-free skin in lichen planus, but no increase was found in the mast cell — nerve contacts. Increased contacts between mast cells and sensory nerves indicate that the elements exist for neurogenic inflammation in psoriatic lesions. These increased contacts are not due to the extensive inflammatory reaction only, because they were not observed in lichen planus lesions.     

玫瑰痤疮的病理生理发病机制研究进展

玫瑰痤疮发病机制尚未完全阐明,目前认为遗传因素、皮肤局部免疫失衡、神经免疫功能和神经血管环路紊乱、皮肤屏障功能异常、微生物菌群失调等均参与了玫瑰痤疮的发生发展。本文综述玫瑰痤疮的病理生理发病机制研究进展。     

Neurogenic inflammation of the airways and skin

According to its original definition, the main feature of neurogenic inflammation is plasma leakage induced by the stimulation of peripheral sensory nerves. The plasma leakage from postcapillary venules is accompanied by increased blood flow due to dilatation of upstream arterioles, and by other phenomena, including leukocyte adhesion and migration. Neurogenic inflammation occurs in the airways, skin, and parts of the intestinal, urinary, and reproductive tract of man and animals, but varies markedly in its magnitude and extent. In skin, neurogenic inflammation is manifested as wheal and flare. Both phenomena are mediated by neuropeptides released from unmyelinated sensory nerve fibers via stimulation of capsaicin-sensitive vanilloid receptors. Substance P is mainly responsible for the plasma leakage, acting via NK-1 receptors present on target blood vessels, whereas calcitonin gene-related peptide and substance P both induce vasodilatation. Sensory neuropeptides also trigger release of histamine from mast cells, which contributes substantially to plasma leakage in the skin, but less so in the airways. The increase in vascular permeability is due to a focal, transient, and fully reversible formation of gaps located between endothelial cell junctions. Neurogenic inflammation can be inhibited by preventing the stimulation of sensory nerves, by depleting them of their neuropeptide transmitters, by presynaptic inhibition of transmitter release, or by blocking neuropeptide receptors. Anti-inflammatory drugs such as β-adrenergic agonists and steroids can reduce neurogenic inflammation by stabilizing endothelial cells.     

Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates

Atopic dermatitis is a chronic inflammatory skin disease characterized by impaired epidermal barrier function, inflammatory infiltration, extensive pruritus and a clinical course defined by symptomatic flares and remissions. The mechanisms of disease exacerbation are still poorly understood. Clinical occurrence of atopic dermatitis is often associated with psychological stress. In response to stress, upregulation of neuropeptide mediators in the brain, endocrine organs, and peripheral nervous system directly affect immune and resident cells in the skin. Lesional and non-lesional skin of patients with atopic dermatitis demonstrates increased mast cells and mast cell-nerve fiber contacts. In the setting of stress, sensory nerves release neuromediators that regulate inflammatory and immune responses, as well as barrier function. Progress towards elucidating these neuroimmune connections will refine our understanding of how emotional stress influences atopic dermatitis. Moreover, psychopharmacologic agents that modulate neuronal receptors or the amplification circuits of inflammation are attractive options for the treatment of not only atopic dermatitis, but also other stress-mediated inflammatory skin diseases.     

β-endorphin modulates lipogenesis in human sebocytes

Proteinase-activated receptors are G-protein-coupled receptors with seven-transmembrane domains activated by serine proteinases. PAR-2 is a receptor for mast cell tryptase, house dust mite allergens, bacterial antigens and trypsin, for example, indicating a role of PAR-2 during inflammation and immune responses. In the skin, PAR-2 is expressed by keratinocytes, endothelial cells, certain immune cells and nerves, suggesting a broad regulatory role of proteases in the skin. Recently, PAR-2 has been demonstrated to be involved in neurogenic inflammation. Therefore, we examined whether neuronal PAR-2 may be involved in pruritus of human skin. The endogenous PAR-2 agonist tryptase was increased up to fourfold in atopic dermatitis (AD) patients. PAR-2 was markedly enhanced on primary afferent nerve fibres in skin biopsies of AD patients. Intracutaneous injection of endogenous PAR-2 agonists provoked enhanced and prolonged itch when applied intralesionally. Interestingly, itch upon mast cell degranulation prevailed despite local antihistamines in AD patients only. Thus, we identified enhanced PAR-2 signalling as a new link between inflammatory and sensory phenomena in AD patients. PAR-2 antagonists, thus, represent a promising therapeutic target for the treatment of cutaneous neurogenic inflammation and pruritus.     

Mite allergen induces allergic dermatitis with concomitant neurogenic inflammation in mouse

Pathogenesis of atopic dermatitis involved the interactions of immune and neuroendocrine systems. Here we describe a mouse model for atopic dermatitis with concomitant neurogenic inflammation, by epicutaneous sensitization with a dust mite allergen. Allergen patching resulted in localized dermatitis characterized by pronounced epidermal hyperplasia and spongiosis, which was associated with infiltration of eosinophils and neutrophils, degranulated mast cells, CD4+ and CD8+ T cells, and dendritic cells. There was increased innervation of calcium gene related peptides and substance P in inflamed skins, interactions between nerve fibers and mast cells were seen, indicating the coexistence of neurogenic inflammation. Splenic T cells produced T helper 2-polarized cytokines in response to allergen stimulation in vitro, indicating systemic allergen sensitization. This is the first report of a mouse model of eczema, accompanied by neurogenic inflammation, which shows close resemblance to human allergic diseases. This work supports the notion that the skin is an important site for the initiation of primary allergen sensitization. Besides, this model may also be useful for study of other stress-associated neuroinflammatory skin disorders such as neurogenic pruritus and psoriasis.     

Further exploring the brain-skin connection: stress worsens dermatitis via substance P-dependent neurogenic inflammation in mice

A neurogenic component in atopy and allergy is evident and potentially of great pathogenic relevance. Stress was recently shown to activate elements of this component and is vividly discussed as a cause of exacerbation. However, to date, scientific proof of stress-induced neuronal plasticity and neuro-immune interaction in atopy or allergy remains lacking. Here we show early evidence that exposure to sound stress and atopic dermatitis-like allergic dermatitis (AD) equipotently raise the number of cutaneous nerve fibers containing the prototypic stress neuropeptide substance P (SP) in mice. Stress increases AD readout parameters by at least 30% (eosinophil infiltration, vascular cell adhesion molecule-positive blood vessels, epidermal thickness). This dramatic pathologic exacerbation is associated with increased neurogenic inflammation (degranulated mast cells; interstitial neuropeptidergic dense core granules, mast cell apoptosis, endothelial gaping). Key features of AD exacerbation could not be induced in mice lacking the neurokinin-1 SP receptor (NK1). Interestingly, stress had no significant additional effect on CD4+ cell number, but shifted the cytokine profile toward TH2 in skin. Thus, we conclude that stress primarily exacerbates AD via SP-dependent cutaneous neurogenic inflammation and subsequent local cytokine shifting and should be considered as a therapeutic target, while it offers a convincing pathogenic explanation to affected patients and their frustrated physicians alike.     

Mast cells,nerves and neuropeptides in atopic dermatitis and nummular eczema

The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.     

Is there a role for mast cells in psoriasis?

Mast cells have traditionally been considered as effector cells in allergy but during the last decade it has been realized that mast cells are essentially involved in the mechanisms of innate and acquired immunity. Upon activation by anaphylactic, piecemeal degranulation or degranulation-independent mechanisms mast cells can secrete rapidly or slowly a number of soluble mediators, such as serine proteinases, histamine, lipid-derived mediators, cytokines, chemokines and growth factors. Mast cells can express cell surface co-stimulatory receptors and ligands, and they can express MHC class II molecules and thereby present antigens. These soluble factors and cell surface molecules can interact with other cells, such as endothelial cells, keratinocytes, sensory nerves, neutrophils, T cell subsets and antigen presenting cells which are essential effectors in the development of skin inflammation. Besides promoting inflammation, mast cells may attempt in some circumstances to suppress the inflammation and epidermal growth but the regulation between suppressive and proinflammatory mechanisms is unclear. Psoriasis is characterized by epidermal hyperplasia and chronic inflammation where tryptase- and chymase-positive MC_TC mast cells are activated early in the developing lesion and later the cells increase in number in the upper dermis with concomitant expression of cytokines and TNF superfamily ligands as well as increased contacts with neuropeptide-containing sensory nerves. Due to the intimate involvement of mast cells in immunity and chronic inflammation the role of mast cells in psoriasis is discussed in this review.     

CGRP-immunoreactive nerves in prurigo nodularis--an exploration of neurogenic inflammation

BACKGROUND: The present study has explored the localization and distribution of calcitonin gene-related peptide (CGRP)-immunoreactive (IR) nerve fibers in prurigo nodularis, especially emphasizing its relationships to mast cells and eosinophils, which all are important contributors to inflammation. METHODS: The exact localization of CGRP in the nerve fibers of prurigo nodularis lesional skin has been clarified by an ultrastructural immunogold labelling technique; and the relationships of CGRP-IR nerve fibers to tryptase-IR mast cells or eosinophil cationic protein (ECP)-IR eosinophils were also investigated by immunofluorescence double-labelling. RESULTS: This ultrastructural study has demonstrated that CGRP immunoreactivity is increased in the dense-core vesicles in the axons of the prurigo nodularis lesional skin; the axons which contain CGRP are, in addition, enlarged and have more dense-core vesicles than the axons which do not contain CGRP. The immunofluorescence investigation demonstrated that tryptase-containing mast cells and ECP-containing eosinophils also are significantly increased in the lesional skin. CONCLUSIONS: The results indicate that certain neurons increasingly express CGRP, which may dynamically result in a neurogenic inflammation in the lesional skin, through vasodilatation, and recruitment and regulation of inflammatory cells, e.g. eosinophils and mast cells.     

Botulinum toxin blocks mast cells and prevents rosacea like inflammation

Background

Rosacea is a chronic inflammatory skin condition whose etiology has been linked to mast cells and the antimicrobial peptide cathelicidin LL-37. Individuals with refractory disease have demonstrated clinical benefit with periodic injections of onabotulinum toxin, but the mechanism of action is unknown.

Itching for an answer: A review of potential mechanisms of scalp itch in psoriasis

Scalp psoriatic itch is a common complaint and often poses a therapeutic challenge. The pathophysiology of this phenomenon is unclear. The unique anatomy of the scalp contains richly innervated hair follicles, abundant vasculature and perifollicular inflammatory cytokines which may all contribute to this common sensory complaint. The mast cell, in particular, is portrayed as one of the main itch conductors for its ability to trigger neurogenic inflammation, activate the peripheral hypothalamic‐pituitary‐adrenal‐axis, process and integrate itch signalling through its interactions with the scalp hair follicles. Herein, we explain and speculate upon potential mechanisms underlying itchy scalp psoriasis, involving interconnections between the neuroimmune, neurovascular and neuroendocrine systems. Many factors may play roles in itchy scalp psoriasis including the scalp hair structure, immune system, endocrine system, nervous system and vascular system. These may warrant further exploration as therapeutic targets that go beyond the application of mere anti‐inflammatory agents.     

Laser treatment of rosacea: a pathoetiological study

OBJECTIVE: To study the effect of laser treatment on rosacea, a common facial skin disease with symptoms of blushing, redness, telangiectasis, papules, pustules, and diffuse swelling of the skin, we focused on the stinging sensation and performed immunohistochemical evaluation of nerve density and neuropeptide expression. DESIGN: Clinical investigation as well as the lactic acid (stinger) test was performed before and 3 months after the treatment with flashlamp pulsed dye laser, when skin biopsy specimens were also taken. SETTING: University hospital. PATIENTS: Thirty-two patients with rosacea, all with positive results from the lactic acid "stinger" test, were treated by flashlamp pulsed dye laser. MAIN OUTCOME MEASURES: The biopsy specimens were taken from the stinger-positive areas in the nasolabial folds, fixed in Lanas fixative (10% formalin and 0.4% picric acid), and analyzed for the expression of protein gene product 9.5 (general nerve marker), substance P, calcitonin gene-related peptide, and vasoactive intestinal polypeptide, using a biotinylated streptavidin technique. RESULTS: Thirty-one patients who were stinger positive before treatment showed decreased scores after treatment, and 1 patient had the same stinger test score before and after treatment. The number of protein gene product 9.5-positive fibers in the epidermis (P< .05) as well as the papillary dermis (P< .01) was decreased. This was also the case for substance P in the papillary dermis (P< .001), whereas no evident difference was noted for vasoactive intestinal polypeptide and calcitonin gene-related peptide. No difference was found for contact between nerves and vessels (factor VIII positive). CONCLUSIONS: Laser treatment of rosacea that destroys small vessels has a good medical relevance because it reduces the unpleasant symptoms of the sensitive skin. A neurogenic etiology of stinging may be possible.