Interaction of human keratinocytes and nerve fiber terminals at the neuro-cutaneous unit

eLife, Год журнала: 2024, Номер 13

Опубликована: Янв. 16, 2024

Traditionally, peripheral sensory neurons are assumed as the exclusive transducers of external stimuli. Current research moves epidermal keratinocytes into focus sensors and transmitters nociceptive non-nociceptive sensations, tightly interacting with intraepidermal nerve fibers at neuro-cutaneous unit. In animal models, cells establish close contacts ensheath neurites. However, ultrastructural morphological mechanistic data examining human keratinocyte-nerve fiber interface sparse. We investigated this exact in skin applying super-resolution array tomography, expansion microscopy, structured illumination microscopy. show keratinocyte ensheathment afferents adjacent connexin 43 native have applied a pipeline based on microscopy to quantify these parameter sections healthy participants versus patients small neuropathy. further derived fully co-culture system, visualizing plaques vitro. Unraveling potential interaction sites advances These findings crucial way decipher mechanisms cutaneous nociception.

Язык: Английский

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Neuro–immuno–endocrinology of the skin: how environment regulates body homeostasis

Nature Reviews Endocrinology, Год журнала: 2025, Номер unknown

Опубликована: Апрель 22, 2025

Язык: Английский

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Keratinocytes: new perspectives in inflammatory skin diseases

Trends in Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

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The involvement of keratinocytes in pruritus of chronic inflammatory dermatosis

Experimental Dermatology, Год журнала: 2024, Номер 33(7)

Опубликована: Июль 1, 2024

Abstract Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis psoriasis. The persistent prolonged nature of pruritus can worsen one's quality life. Keratinocytes (KCs), the predominant cells epidermis, have been confirmed to interact with sensory neurons immune be involved diseases associated pruritus. Initially, KCs form a unique synapse‐like connection within serving as structural foundation for their interaction. Additionally, several receptors, toll‐like receptors protease‐activated receptor 2, expressed on KCs, become activated an milieu. On one hand, sources pro‐inflammatory cytokines neurotrophic factors, such adenosine triphosphate, thymic stromal lymphopoietin, nerve growth factor, which directly or indirectly participate stimulating neurons, thereby contributing itch sensations. other also function primary transducers alongside intraepidermal endings, initiating pruritic responses. This review summarizes current literature highlights critical role development persistence disorders.

Язык: Английский

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Elevated interleukin-8 expression by skin fibroblasts as a potential contributor to pain in women with Fabry disease

PLoS ONE, Год журнала: 2024, Номер 19(4), С. e0300687 - e0300687

Опубликована: Апрель 9, 2024

Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain both sexes as an early FD symptom unknown pathophysiology. We aimed at elucidating link between skin cells nociceptor sensitization contributing sex-associated manner. used cultured keratinocytes fibroblasts 27 adult patients 20 healthy controls. Epidermal dermal were immunoreacted evaluate Gb3 load. Gene expression analysis pain-related ion channels pro-inflammatory cytokines was performed fibroblasts. further investigated electrophysiological properties induced pluripotent stem cell (iPSC) derived sensory-like neurons man with incubated interleukin 8 (IL-8) or fibroblast supernatant vitro model system. Keratinocytes displayed no intracellular, but membrane-bound deposits. In contrast, showed intracellular revealed higher potassium intermediate/small conductance calcium-activated channel 3.1 (KCa 3.1, KCNN4 ) both, men women compared Additionally, cytokine increased IL-8 RNA levels only female Patch-clamp studies reduced rheobase currents for iPSC neuron lines FD. conclude that deposition patient may KCa3.1 activity secretion. This result cutaneous potential mechanism phenotype.

Язык: Английский

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Keratinocyte-derived exosomes in painful diabetic neuropathy

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 22, 2024

ABSTRACT Painful diabetic neuropathy (PDN) is a challenging complication of diabetes with patients experiencing painful and burning sensation in their extremities. Existing treatments provide limited relief without addressing the underlying mechanisms disease. PDN involves gradual degeneration nerve fibers skin. Keratinocytes, most abundant epidermal cell type, are closely positioned to cutaneous terminals, suggesting possibility bi-directional communication. Exosomes small extracellular vesicles released from many types that mediate The role keratinocyte-derived exosomes (KDEs) influencing signaling between skin terminals contribution genesis has not been explored. In this study, we characterized KDEs well-established high-fat diet (HFD) mouse model using primary adult keratinocyte cultures. We obtained highly enriched through size exclusion chromatography then analyzed molecular cargo proteomic analysis RNA sequencing. found significant differences protein microRNA content HFD compared control mice on regular (RD), including pathways involved axon guidance synaptic transmission. Additionally, an vivo conditional vesicle (EV) reporter model, demonstrated epidermal-originating GFP-tagged retrogradely trafficked into DRG neuron body. Overall, our study presents potential novel mode communication keratinocytes neurons skin, revealing possible for contributing axonal underlies neuropathic pain PDN. Moreover, therapeutic targets developing more effective, disease-modifying, better-tolerated topical interventions suffering PDN, one common untreatable peripheral neuropathies.

Язык: Английский

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Activation of G protein gated inwardly rectifying potassium (GIRK) channels in keratinocytes mediates peripheral kappa opioid receptor-mediated antinociception.

Neuropharmacology, Год журнала: 2025, Номер unknown, С. 110326 - 110326

Опубликована: Янв. 1, 2025

Язык: Английский

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TRPV1 is the burner

Pain, Год журнала: 2025, Номер unknown

Опубликована: Фев. 5, 2025

Язык: Английский

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Exploring the role of exosomes in diabetic neuropathy: From molecular mechanisms to therapeutic potential

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 185, С. 117959 - 117959

Опубликована: Март 8, 2025

Язык: Английский

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Wnt5a in keratinocytes contributes to complex regional pain syndrome through the activation of NR2B and MMP9 in rats

Regional Anesthesia & Pain Medicine, Год журнала: 2025, Номер unknown, С. rapm - 106139

Опубликована: Март 12, 2025

Background Complex regional pain syndrome (CRPS) is a chronic condition characterized by inflammatory features, though the underlying mechanisms remain partly understood. Our study examined whether Wnt5a in skin keratinocytes contributes to CRPS-related hypersensitivity activating downstream N-methyl-D-aspartate receptor subunit 2B (NR2B) and matrix metalloproteinase-9 (MMP9) signaling rats. Methods We developed cell-culture model mimic local inflammation of CRPS rat post-ischemia experienced patients. Mechanical heat thresholds hind paw were measured using an electronic von Frey apparatus radiant device. Western blotting immunofluorescence used examine expressions NR2B MMP9 dorsal root ganglion (DRG), staining connexin 43 (Cx43) protein gene product 9.5 (PGP9.5) conducted explore interaction between nerve fibers skin. Results In cell culture, was expressed contributed cellular injury increasing levels MMP9. The mechanical decreased rats, indicating increased sensitivity. inhibition alleviated these hypersensitivities. High Cx43 PGP9.5 observed epidermis suggesting that may contribute CRPS. Additionally, upregulations DRG further exacerbate pain. Conclusions Skin play essential role pathophysiology increase sensitivity upregulating MMP9, thereby contributing

Язык: Английский

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