Jean-Luc Carré

Influence of sensory neuropeptides on human cutaneous wound healing process

BACKGROUND Close interactions exist between primary sensory neurons of the peripheral nervous system (PNS) and skin cells. The PNS may be implicated in the modulation of different skin functions as wound healing. OBJECTIVE Study the influence of sensory neurons in human cutaneous wound healing. METHODS We incubated injured human skin explants either with rat primary sensory neurons from dorsal root ganglia (DRG) or different neuropeptides (vasoactive intestinal peptide or VIP, calcitonin gene-related peptide or CGRP, substance P or SP) at various concentrations. Then we evaluated their effects on the proliferative and extracellular matrix (ECM) remodeling phases, dermal fibroblasts adhesion and differentiation into myofibroblasts. RESULTS Thus, DRG and all studied neuromediators increased fibroblasts and keratinocytes proliferation and act on the expression ratio between collagen type I and type III in favor of collagen I, particularly between the 3rd and 7th day of culture. Furthermore, the enzymatic activities of matrix metalloprotesases (MMP-2 and MMP-9) were increased in the first days of wound healing process. Finally, the adhesion of human dermal fibroblasts and their differentiation into myofibroblasts were promoted after incubation with neuromediators. Interestingly, the most potent concentrations for each tested molecules, were the lowest concentrations, corresponding to physiological concentrations. CONCLUSION Sensory neurons and their derived-neuropeptides are able to promote skin wound healing.

TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization

ABSTRACTCutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

Pathophysiological Study of Sensitive Skin

Sensitive skin is a clinical syndrome characterized by the occurrence of unpleasant sensations, such as pruritus, burning or pain, in response to various factors, including skincare products, water, cold, heat, or other physical and/or chemical factors. Although these symptoms suggest inflammation and the activation of peripheral innervation, the pathophysiogeny of sensitive skin remains unknown. We systematically analysed cutaneous biopsies from 50 healthy women with non-sensitive or sensitive skin and demonstrated that the intraepidermal nerve fibre density, especially that of peptidergic C-fibres, was lower in the sensitive skin group. These fibres are involved in pain, itching and temperature perception, and their degeneration may promote allodynia and similar symptoms. These results suggest that the pathophysiology of skin sensitivity resembles that of neuropathic pruritus within the context of small fibre neuropathy, and that environmental factors may alter skin innervation.

Self-maintenance of neurogenic inflammation contributes to a vicious cycle in skin.

Cutaneous neurogenic inflammation (CNI) is frequently associated with skin disorders. CNI is not limited to the retrograde signalling of nociceptive sensory nerve endings but can instead be regarded as a multicellular phenomenon. Thus, soluble mediators participating in communication among sensory nerves, skin and immune cells are key components of CNI. These interactions induce the self‐maintenance of CNI, promoting a vicious cycle. Certain G protein‐coupled receptors (GPCRs) play a prominent role in these cell interactions and contribute to self‐maintenance. Protease‐activated receptors 2 and 4 (PAR‐2 and PAR‐4, respectively) and Mas‐related G protein‐coupled receptors (Mrgprs) are implicated in the synthesis and release of neuropeptides, proteases and soluble mediators from most cutaneous cells. Regulation of the expression and release of these mediators contributes to the vicious cycle of CNI. The authors propose certain hypothetical therapeutic options to interrupt this cycle, which might reduce skin symptoms and improve patient quality of life.

Role of neuropeptides, neurotrophins, and neurohormones in skin wound healing.

Due to the close interactions between the skin and peripheral nervous system, there is increasing evidence that the cutaneous innervation is an important modulator of the normal wound healing process. The communication between sensory neurons and skin cells involves a variety of molecules (neuropeptides, neurohormones, and neurotrophins) and their specific receptors expressed by both neuronal and nonneuronal skin cells. It is well established that neurotransmitters and nerve growth factors released in skin have immunoregulatory roles and can exert mitogenic actions; they could also influence the functions of the different skin cell types during the wound healing process.

Two-photon microscopy of dermal innervation in a human re-innervated model of skin

When skin is injured, innervation can be severely disrupted. The subsequent re‐innervation processes are poorly understood notably because of the inability to image the full meandering course of nerves with their ramifications and endings from histological slices. In this letter, we report on two‐photon excitation fluorescence (TPEF) microscopy of entire human skin explants re‐innervated by rodent sensory neurons labelled with the styryl dye FM1‐43. TPEF imaging of nerve fibres to a depth up to roughly 300 μm within the dermis was demonstrated, allowing three‐dimensional reconstruction of the neural tree structure. Endogenous second‐harmonic imaging of type I fibrillar collagen was performed in parallel to TPEF imaging using the same nonlinear microscope, revealing the path of the nerves through the dermis.

Activation of primary sensory neurons by the topical application of capsaicin on the epidermis of a re-innervated organotypic human skin model.

Using an ex vivo skin‐nerve preparation, skin and nerve cells were reconstituted into a single unit and maintained in a nutrient medium bath until required experimentally. Our objective was to use the epidermis as a relay for the induction of an electric current to the neurons following the topical application of capsaicin on the skin epidermis of the skin explant, an agonist of the TRPV1 channel implicated in pruritus and pain. After 10–20 days of coculture to form the re‐innervated skin model, we applied a solution of capsaicin directly on the epidermis of the skin explant (4 μm). The resulting current was recorded using a path‐clamp technique on the neuronal fibres. Following the topical application of capsaicin, spontaneous activity was triggered, as characterised by repetitive spikes with periods of 125, 225 or 275 ms. This study demonstrates that the skin explant and nerve cells preparation may receive stimuli and be used to screen molecules or to study signal transmission.

Placebo and nocebo effects as major components of the treatment of itch.

In her interesting viewpoint, Andrea Evers underlines how expectations and learned immune function can optimize dermatological treatments through the placebo effect or induce opposite effects through nocebo effects.[1] Placebo and nocebo effects are positive or negative treatment effects that are a consequence not of the treatment itself, but exclusively of the patient’s expectations and beliefs about a more or less beneficial treatment outcome in terms of efficacy, safety, usability or side effects.[2]

The presence of monoclonal gammopathy in Ph-negative myeloproliferative neoplasms is associated with a detrimental effect on outcomes

Abstract Many case reports have indicated the occurrence of monoclonal gammopathy of uncertain significance (MGUS) or multiple myeloma (MM) in patients with Ph-negative myeloproliferative neoplasms (MPN), but few cohorts of patients have been published. This study concerns 667 patients newly diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) who were tested for monoclonal (M) protein at diagnosis (13.9% of patients). The overall survival of patients with M protein was dramatically lower than that of patients without M protein (12.7 versus 22.4 years; p = .0132). Univariate analysis identified the presence of M protein as a potential risk factor for the secondary occurrence of myelofibrosis (p = .02), myelodysplastic syndrome (p = .043), and MM/Waldenstrom macroglobulinemia (p < .0001). Our cohort shows that the presence of M proteins in patients with PV or ET leads to a poor prognosis. We believe that testing for M protein could help practicians to identify such patients.

Clinical characteristics of aquagenic pruritus in patients with myeloproliferative neoplasms

Aquagenic pruritus (AP) is a diffuse itching sensation that develops immediately after water contact without any visible skin changes. AP is classically associated with polycythemia vera (PV), a BCR-ABL1-negative myeloproliferative neoplasm (MPN), and can precede the diagnosis of the disease1,2. Alternatively, AP can be drug-induced or associated with various disorders (e.g., myelodysplastic syndrome, hypereosinophilic syndrome, and juvenile xanthogranuloma)3,4. This article is protected by copyright. All rights reserved.