Sensitive Skin: Lessons From Transcriptomic Studies

In 2016, a special interest group from the International Forum for the Study of Itch defined sensitive skin (SS) as a syndrome that manifests with the occurrence of unpleasant sensations (stinging, burning, pain, pruritus, and tingling sensations) after stimuli that should not cause a reaction, such as water, cold, heat, or other physical and/or chemical factors. The pathophysiology of sensitive skin is still poorly understood, but the symptoms described suggest inflammation and peripheral innervation. Only two publications have focused on sensitive skin transcriptomics. In the first study, the authors performed a microarray comparison of SS and non-sensitive skin (NSS) samples and showed differences in the expression of numerous genes in SS and NSS samples. Moreover, in the SS samples, two clusters of genes were identified, including upregulated and downregulated genes, compared to NSS samples. These results provide some interesting clues for the understanding of the pathophysiology of SS. The second study compared SS and NSS samples using RNA-seq assays. This method allowed the identification of long non-coding RNAs (lncRNAs) and differentially expressed mRNAs and provided a comprehensive profile in subjects with SS. The results showed that a wide range of genes may be involved in the pathogenesis of SS and suggested pathways that could be associated with them. In this paper, we discuss these two studies in detail and show how transcriptomic studies can help understand the pathophysiology of sensitive skin. We call for new transcriptomic studies on larger populations to be conducted before putative pathogenic mechanisms can be detected and analyzed to achieve a better understanding of this complex condition

Régulation neuro-endocrine de l'hématopoïèse (rôle de la Substance P et de son dérivé, la Substance P(1-4), dans la régulation négative de l'érythropoïèse dans la polyglobulie de Vaquez)

Il existe une communication bidirectionnelle entre les systèmes nerveux et hématopoïétique, médiée par des mécanismes complexes impliquant la libération de facteurs solubles et la présence de récepteurs spécifiques. La substance P (SP), tachykinine de li acides aminés, est un exemple type de neuropeptide synthétisé et libéré dans la moelle osseuse, capable d agir sur l hématopoïèse. Des métabolites comme la SP(l-4), issus de la dégradation de la SP par des peptidases présentes dans la moelle, sont également présents et actifs. Le but de ce travail a été de déterminer l action de la SP et de la SP(l-4) dans un contexte d érythropoïèse pathologique comme celle caractérisant la polyglobulie de Vaquez (PV). La PV est un syndrome myéloprolifératif chronique, secondaire à l expansion clonale de cellules souches, qui peut être mise e évidence in vitro par une pousse spontanée, c est-à-dire sans addition de facteurs de croissance, des progéniteurs érythroblastiques issus de moelle ou de sang. Les résultats montrent que ces deux molécules sont capables d inhiber efficacement et à des concentrations physiologiques, la pousse spontanée, en agissant directement sur les progéniteurs érythroïdes par une voie dépendante d un récepteur de type NK-1R pour la SP, et l implication d un autre récepteur couplé à des protéines G (RCPG) pour la SP(l-4). L expression majoritaire de la forme tronquée du NK-lR sur les progéniteurs érythroïdes de PV suggère le rôle préférentiel de ce récepteur dans l action de la SP. Ces différences de voies membranaires entre les deux molécules sont sans doute à l origine de l action différentielle sur la PKC et sur les mouvements calciques intracellulaires. Pour la SP comme pour la SP( l-4), cette inhibition se traduit par une diminution de la différenciation érythroïde terminale et une augmentation de la mort cellulaire. L implication du monoxyde d azote ou NO ( nitric oxide ) dans la transduction du signal inhibiteur de la SP et de la SPU -4) constitue une étape importante dans l analyse des mécanismes intracellulaires impliqués dans ces deux processus. L adhésion cellulaire est un processus physiologique indispensable à la survie et à la prolifération des cellules in vitro et in vivo. Nous montrons que l inhibition exercée par la SP et la SP(l-4) sur les cellules de PV, n est pas la conséquence d une rupture de cette adhésion. Outre, cette action in vitro, la SP est présente en quantité plus importante dans le sérum de patients atteints de PV, et n est pas corrélée avec la présence de fibrose. Nous pensons que ces données reflètent un mécanisme mis en place par l organisme pour maintenir l homéostasie chez ces patients. Ce travail s inscrit dans l optique d identifier les molécules capables d inhiber la pousse spontanée des progéniteurs érythroïdes de PV et de comprendre les mécanismes impliqués dans cet effet inhibiteur ainsi que ceux impliqués dans la pousse spontanée en général.The hematopoietic and nervous systems communicate bidirectionally through the release of soluble factors and specific receptors. Substance P (SP), an undecapeptide belonging to the tachykinin family, is an example 0f a neurotransmitter that could be synthetized and released in the bone marrow (BM). SP could act as a hematopoietic modulator and can be further digested by peptidases ubiquitously expressed in BM. SP fragments as SP(1 -4) could exert hematopoietic regulation too. The aim of this study was to determine effect of SP and its derivate, SP( 1-4), on pathologie erythropoiesis. Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by the abnormal proliferation of multipotent hematopoietic progenitor. Endogenous erythroid colonies (EEC) formation is the biological hallmark of the PV. Resuits obtained show that SP and SP(1-4), at physiological concentration, are potent inhibitors of EEC formation by direct action on erythroid progenitors. SP-induced inhibition is mediated by a NK-1R-type dependent mechanism and another G coupled-protein receptor (GPCR) for SP( 1-4) effect. High expression of the truncated form of NK-1 R on PV erythroid progenitor suggests preferential implication in the SP effect, Difference in membranar signaling pathway for SP and SP(l-4) could explain the differential implication of PKC and intracellular calcium rise, However, for both molecules, inhibitory effect is characterized by inhibition of terminal erythroid differentiation and increase cell death. Nitric oxide (NO) implication in signal transduction constitutes an important information to explain these mechanisms. Furthermore, inhibitory effect of SP and SP(1-4) is independent of action on adhesion molecules and rupture of cell adhesion of PV progenitors. In addition to its role in vitro, high concentrations of SP were detected in PV patients sera and was not correlated with fibrosis. We propose that this phenomenon reflect a mechanism induces by the organism to maintain homeostasis in PV patients. This work participates to the identification of new molecules able to inhibit spontaneous growth of PV erythroid progenitor and in the understanding of mechanisms implicated in the EEC formation and inhibition of this phenomenon.BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Sensitive Skin: Lessons From Transcriptomic Studies

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Expression of neuroserpin, a selective inhibitor of tissue-type plasminogen activator in the human skin

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Re‐innervation of human skin by rat dorsal root ganglia permits to study interactions between sensory nerve fibres and native human dermal mast cells ex vivo

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Do Merkel complexes initiate mechanical itch?

Abstract Itch is a common sensation which is amenable to disabling patients' life under pathological and chronic conditions. Shared assertion easily limits itch to chemical itch, without considering mechanical itch and alloknesis, its pathological counterpart. However, in recent years, our understanding of the mechanical itch pathway, particularly in the central nervous system, has been enhanced. In addition, Merkel complexes, conventionally considered as tactile end organs only responsible for light touch perception due to Piezo2 expressed by both Merkel cells and SA1 Aβ‐fibres ‐ low threshold mechanical receptors (LTMRs) ‐, have recently been identified as modulators of mechanical itch. However, the tactile end organs responsible for initiating mechanical itch remain unexplored. The consensus is that some LTMRs, either SA1 Aβ‐ or A∂‐ and C‐, are cutaneous initiators of mechanical itch, even though they are not self‐sufficient to finely detect and encode light mechanical stimuli into sensory perceptions, which depend on the entire hosting tactile end organ. Consequently, to enlighten our understanding of mechanical itch initiation, this article discusses the opportunity to consider Merkel complexes as potential tactile end organs responsible for initiating mechanical itch, under both healthy and pathological conditions. Their unsuspected modulatory abilities indeed show that they are tuned to detect and encode light mechanical stimuli leading to mechanical itch, especially as they host not only SA1 Aβ‐LTMRs but also A∂‐ and C‐fibres

Aquagenic pruritus in essential thrombocythemia is associated with a higher risk of thrombosis

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La pollution atmosphérique contribue à la rupture de la barrière cutanée et ralentit la croissance neuronale

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Differences between aquagenic and non‐aquagenic pruritus in myeloproliferative neoplasms: An observational study of 500 patients

Abstract Background Pruritus is a frequent symptom experienced by patients with myeloproliferative neoplasms (MPN). Aquagenic pruritus (AP) is the most common type. The Myeloproliferative Neoplasm‐Symptom Assessment Form Total Symptom Score (MPN‐SAF TSS) self‐report questionnaires were distributed to MPN patients before consultations. Objectives The aim of this study was to assess clinical incidence (phenotypical evolution and response to treatment) of pruritus, especially AP, in MPN patients during their follow‐ups. Patients and Methods We collected 1444 questionnaires from 504 patients [54.4% essential thrombocythaemia (ET) patients, 37.7% polycythaemia vera (PV) patients, and 7.9% primary myelofibrosis (PMF) patients]. Results Pruritus was reported by 49.8% of the patients, including 44.6% of AP patients, regardless of type of MPN or driver mutations. Patients suffering from pruritus were more symptomatic and had a higher rate of evolution into myelofibrosis/acute myeloid leukaemia (19.5% vs. 9.1%, OR = 2.42 [1.39; 4.32], p = 0.0009) than MPN patients without pruritus. Patients with AP had the highest pruritus intensity values ( p = 0.008) and a higher rate of evolution (25.9% vs. 14.4%, p = 0.025, OR = 2.07) than patients with non‐AP. Disappearance of pruritus was observed in only 16.7% of AP cases, compared to 31.7% of cases with other types of pruritus ( p < 0.0001). Ruxolitinib and hydroxyurea were the most effective drugs to reduce AP intensity. Conclusions In this study, we demonstrate the global incidence of pruritus across all MPN. Pruritus, especially AP, which is a major constitutional symptom observed in MPN, should be assessed in all MPN patients due to higher symptom burden and higher risk of evolution