Role of Keratinocytes in Sensitive Skin

Sensitive skin is a clinical syndrome defined by the occurrence of unpleasant sensations such as burning, stinging, tingling, pricking, or itching in response to various normally innocuous physical, chemical, and thermal stimuli. These particular symptoms have led the consideration of a potential dysfunction of the intra-epidermal nerve fibers (IENF) that are responsible for pain, temperature, and itch perception. This neuronal hypothesis has just been reinforced by recent studies suggesting that sensitive skin could become assimilated to small fiber neuropathy. Meanwhile, the involvement of keratinocytes, the pre-dominant epidermal cell type, has so far mainly been considered because of their role in the epidermal barrier. However, keratinocytes also express diverse sensory receptors present on sensory neurons, such as receptors of the transient receptor potential (TRP) family, including Transient Receptor Potential Vallinoid 1 (TRPV1), one of the main transducers of painful heat which is also involved in itch transduction, and Transient Receptor Potential Vallinoid 4 (TRPV4) which is depicted as a heat sensor. While TRPV1 and TRPV4 are expressed both by sensory neurons and keratinocytes, it has recently been demonstrated that the specific and selective activation of TRPV1 on keratinocytes is sufficient to induce pain. Similarly, the targeted activation of keratinocyte-expressed TRPV4 elicits itch and the resulting scratching behavior. So, contrary to classical conception, the IENF are not the exclusive transducers of pain and itch. In light of these recent advances, this review proposes to consider the putative role of epidermal keratinocytes in the generation of the unpleasant sensations characteristic of sensitive skin syndrome

NRAS Q61R , BRAF V600E immunohistochemistry: a concomitant tool for mutation screening in melanomas

International audienceThe determination of NRAS and BRAF mutation status is a major requirement in the treatment of patients with metastatic melanoma. Mutation specific antibodies against NRAS(Q61R) and BRAF(V600E) proteins could offer additional data on tumor heterogeneity. The specificity and sensitivity of NRAS(Q61R) immunohistochemistry have recently been reported excellent. We aimed to determine the utility of immunohistochemistry using SP174 anti-NRAS(Q61R) and VE1 anti-BRAF(V600E) antibodies in the theranostic mutation screening of melanomas. 142 formalin-fixed paraffin-embedded melanoma samples from 79 patients were analyzed using pyrosequencing and immunohistochemistry. 23 and 26 patients were concluded to have a NRAS-mutated or a BRAF-mutated melanoma respectively. The 23 NRAS (Q61R) and 23 BRAF (V600E) -mutant samples with pyrosequencing were all positive in immunohistochemistry with SP174 antibody and VE1 antibody respectively, without any false negative. Proportions and intensities of staining were varied. Other NRAS (Q61L) , NRAS (Q61K) , BRAF (V600K) and BRAF (V600R) mutants were negative in immunohistochemistry. 6 single cases were immunostained but identified as wild-type using pyrosequencing (1 with SP174 and 5 with VE1). 4/38 patients with multiple samples presented molecular discordant data. Technical limitations are discussed to explain those discrepancies. Anyway we could not rule out real tumor heterogeneity. In our study, we showed that combining immunohistochemistry analysis targeting NRAS(Q61R) and BRAF(V600E) proteins with molecular analysis was a reliable theranostic tool to face challenging samples of melanoma

Caractérisation des zones de contact entre kératinocytes et neurones sensoriels

The skin is a sensory organ containing a wide variety of sensory end organs. Among them, intraepidermal free nerve endings, described in the intercellular spaces of the epidermis, especially keratinocytes, are considered as conveying information about temperature, pain and itch (article 1). Using confocal laser-scanning microscopy in human skin biopsies, we demonstrate that nerve fibres also progress in keratinocyte cytoplasmic tunnels. Contacts between keratinocytes and sensory neurons are also much more intimate than expected (article 2). It has only recently been demonstrated that keratinocytes can transduce nociceptive information. To understand the mechanisms underlying keratinocyte communication with sensory neurons, we performed co-cultures of keratinocytes and sensory neurons. Using multi-modal imaging, molecular and functional approaches, we reveal the existence of en passant chemical synapses between epidermal keratinocytes and intra-epidermal nerve endings (article 3). This discovery of synaptic structures is a paradigm shift that leads to consider the whole epidermis as a sensory epithelium. Finally, a review including our results shows how the physical contacts between sensory neurons and epidermal cells contribute to the dialogue between the skin, the nervous system and the immune system, anatomically defining the neuro-immuno-cutaneous system (article 4).La peau est un organe sensoriel, par définition richement innervé. Parmi les divers récepteurs cutanés, les fibres nerveuses libres intra-épidermiques sont considérées comme percevant directement les informations douloureuses et thermiques ou encore le prurit (article 1). Elles sont classiquement décrites comme cheminant entre les cellules épidermiques, en particulier les kératinocytes. L’étude de biopsies cutanées en microscopie confocale nous permet dans un premier temps de démontrer que ces fibres progressent également dans des tunnels kératinocytaires, révélant ainsi que les rapports entre kératinocytes et fibres nerveuses sont plus intimes que précédemment décrits (article 2). Alors qu’il a été récemment démontré que les kératinocytes peuvent également percevoir des informations nociceptives et activer ces fibres nerveuses, nous avons par ailleurs développé un modèle de co-culture de kératinocytes et de neurones sensoriels afin de caractériser les modalités de communication entre ces cellules. En nous appuyant sur une triple approche morphologique, moléculaire et fonctionnelle, nous révélons l’existence de synapses en passant entre les kératinocytes et les neurones sensoriels (article 3). La découverte de ces structures synaptiques constitue un changement de paradigme qui invite à considérer l’épiderme dans son ensemble comme un épithélium sensoriel. Dans un troisième temps, une revue de la littérature, incluant nos résultats, explore la façon dont les contacts entre les neurones sensoriels et les différentes cellules épidermiques contribuent au dialogue entre la peau, le système nerveux et le système immunitaire, définissant anatomiquement le système neuro-immuno-cutané (article 4)

Characterization of contact areas between keratinocytes and sensory neurons

La peau est un organe sensoriel, par définition richement innervé. Parmi les divers récepteurs cutanés, les fibres nerveuses libres intra-épidermiques sont considérées comme percevant directement les informations douloureuses et thermiques ou encore le prurit (article 1). Elles sont classiquement décrites comme cheminant entre les cellules épidermiques, en particulier les kératinocytes. L’étude de biopsies cutanées en microscopie confocale nous permet dans un premier temps de démontrer que ces fibres progressent également dans des tunnels kératinocytaires, révélant ainsi que les rapports entre kératinocytes et fibres nerveuses sont plus intimes que précédemment décrits (article 2). Alors qu’il a été récemment démontré que les kératinocytes peuvent également percevoir des informations nociceptives et activer ces fibres nerveuses, nous avons par ailleurs développé un modèle de co-culture de kératinocytes et de neurones sensoriels afin de caractériser les modalités de communication entre ces cellules. En nous appuyant sur une triple approche morphologique, moléculaire et fonctionnelle, nous révélons l’existence de synapses en passant entre les kératinocytes et les neurones sensoriels (article 3). La découverte de ces structures synaptiques constitue un changement de paradigme qui invite à considérer l’épiderme dans son ensemble comme un épithélium sensoriel. Dans un troisième temps, une revue de la littérature, incluant nos résultats, explore la façon dont les contacts entre les neurones sensoriels et les différentes cellules épidermiques contribuent au dialogue entre la peau, le système nerveux et le système immunitaire, définissant anatomiquement le système neuro-immuno-cutané (article 4).The skin is a sensory organ containing a wide variety of sensory end organs. Among them, intraepidermal free nerve endings, described in the intercellular spaces of the epidermis, especially keratinocytes, are considered as conveying information about temperature, pain and itch (article 1). Using confocal laser-scanning microscopy in human skin biopsies, we demonstrate that nerve fibres also progress in keratinocyte cytoplasmic tunnels. Contacts between keratinocytes and sensory neurons are also much more intimate than expected (article 2). It has only recently been demonstrated that keratinocytes can transduce nociceptive information. To understand the mechanisms underlying keratinocyte communication with sensory neurons, we performed co-cultures of keratinocytes and sensory neurons. Using multi-modal imaging, molecular and functional approaches, we reveal the existence of en passant chemical synapses between epidermal keratinocytes and intra-epidermal nerve endings (article 3). This discovery of synaptic structures is a paradigm shift that leads to consider the whole epidermis as a sensory epithelium. Finally, a review including our results shows how the physical contacts between sensory neurons and epidermal cells contribute to the dialogue between the skin, the nervous system and the immune system, anatomically defining the neuro-immuno-cutaneous system (article 4)

Caractérisation des zones de contact entre kératinocytes et neurones sensoriels

The skin is a sensory organ containing a wide variety of sensory end organs. Among them, intraepidermal free nerve endings, described in the intercellular spaces of the epidermis, especially keratinocytes, are considered as conveying information about temperature, pain and itch (article 1). Using confocal laser-scanning microscopy in human skin biopsies, we demonstrate that nerve fibres also progress in keratinocyte cytoplasmic tunnels. Contacts between keratinocytes and sensory neurons are also much more intimate than expected (article 2). It has only recently been demonstrated that keratinocytes can transduce nociceptive information. To understand the mechanisms underlying keratinocyte communication with sensory neurons, we performed co-cultures of keratinocytes and sensory neurons. Using multi-modal imaging, molecular and functional approaches, we reveal the existence of en passant chemical synapses between epidermal keratinocytes and intra-epidermal nerve endings (article 3). This discovery of synaptic structures is a paradigm shift that leads to consider the whole epidermis as a sensory epithelium. Finally, a review including our results shows how the physical contacts between sensory neurons and epidermal cells contribute to the dialogue between the skin, the nervous system and the immune system, anatomically defining the neuro-immuno-cutaneous system (article 4).La peau est un organe sensoriel, par définition richement innervé. Parmi les divers récepteurs cutanés, les fibres nerveuses libres intra-épidermiques sont considérées comme percevant directement les informations douloureuses et thermiques ou encore le prurit (article 1). Elles sont classiquement décrites comme cheminant entre les cellules épidermiques, en particulier les kératinocytes. L’étude de biopsies cutanées en microscopie confocale nous permet dans un premier temps de démontrer que ces fibres progressent également dans des tunnels kératinocytaires, révélant ainsi que les rapports entre kératinocytes et fibres nerveuses sont plus intimes que précédemment décrits (article 2). Alors qu’il a été récemment démontré que les kératinocytes peuvent également percevoir des informations nociceptives et activer ces fibres nerveuses, nous avons par ailleurs développé un modèle de co-culture de kératinocytes et de neurones sensoriels afin de caractériser les modalités de communication entre ces cellules. En nous appuyant sur une triple approche morphologique, moléculaire et fonctionnelle, nous révélons l’existence de synapses en passant entre les kératinocytes et les neurones sensoriels (article 3). La découverte de ces structures synaptiques constitue un changement de paradigme qui invite à considérer l’épiderme dans son ensemble comme un épithélium sensoriel. Dans un troisième temps, une revue de la littérature, incluant nos résultats, explore la façon dont les contacts entre les neurones sensoriels et les différentes cellules épidermiques contribuent au dialogue entre la peau, le système nerveux et le système immunitaire, définissant anatomiquement le système neuro-immuno-cutané (article 4)

Anatomical contacts between sensory neurons and epidermal cells: an unrecognized anatomical network for neuro-immuno-cutaneous crosstalk

Abstract Sensory neurons innervating the skin are conventionally thought to be the sole transducers of touch, temperature, pain and itch. However, recent studies have shown that keratinocytes – like Merkel cells – act as sensory transducers, whether for innocuous or noxious mechanical, thermal or chemical stimuli, and communicate with intraepidermal free nerve endings via chemical synaptic contacts. This paradigm shift leads to consideration of the whole epidermis as a sensory epithelium. Sensory neurons additionally function as an efferent system. Through the release of neuropeptides in intimate neuroepidermal contact areas, they contribute to epidermal homeostasis and to the pathogenesis of inflammatory skin diseases. To counteract the dogma regarding neurocutaneous interactions, seen exclusively from the perspective of soluble and spreading mediators, this review highlights the essential contribution of the unrecognized anatomical contacts between sensory neurons and epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells), which take part in the reciprocal dialogue between the skin, nervous system and immune system

Valeur pronostique de l'expression de VEGF, VEGFR-1, VEGFR-2, neuropiline 1 et HF-1a dans le cancer de la prostate cliniquement localisé (étude rétrospective sur 113 patients avec et sans rechute à distance après prostatectomie radicale)

BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

Intraepidermal nerve fibres are not the exclusive tranducers of nociception

International audienc

Lifting the veil on the keratinocyte contribution to cutaneous nociception

International audienceAbstract Cutaneous nociception is essential to prevent individuals from sustaining injuries. According to the conventional point of view, the responses to noxious stimuli are thought to be exclusively initiated by sensory neurons, whose activity would be at most modulated by keratinocytes. However recent studies have demonstrated that epidermal keratinocytes can also act as primary nociceptive transducers as a supplement to sensory neurons. To enlighten our understanding of cutaneous nociception, this review highlights recent and relevant findings on the cellular and molecular elements that underlie the contribution of epidermal keratinocytes as nociceptive modulators and noxious sensors, both under healthy and pathological conditions