2020.03.19

Complementary roles of murine NaV1.7, NaV1.8 and NaV1.9 in acute itch signalling

Helen Kühn*, Leonie KappesKatharina WolfLisa GebhardtMarkus F. NeurathPeter ReehMichael J. M. Fischer & Andreas E. Kremer

Abstract

Acute pruritus occurs in various disorders. Despite severe repercussions on quality of life treatment options remain limited. Voltage-gated sodium channels (NaV) are indispensable for transformation and propagation of sensory signals implicating them as drug targets. Here, NaV1.7, 1.8 and 1.9 were compared for their contribution to itch by analysing NaV-specific knockout mice. Acute pruritus was induced by a comprehensive panel of pruritogens (C48/80, endothelin, 5-HT, chloroquine, histamine, lysophosphatidic acid, trypsin, SLIGRL, β-alanine, BAM8-22), and scratching was assessed using a magnet-based recording technology. We report an unexpected stimulus-dependent diversity in NaV channel-mediated itch signalling. NaV1.7−/− showed substantial scratch reduction mainly towards strong pruritogens. NaV1.8−/− impaired histamine and 5-HT-induced scratching while NaV1.9 was involved in itch signalling towards 5-HT, C48/80 and SLIGRL. Furthermore, similar microfluorimetric calcium responses of sensory neurons and expression of itch-related TRP channels suggest no change in sensory transduction but in action potential transformation and conduction. The cumulative sum of scratching over all pruritogens confirmed a leading role of NaV1.7 and indicated an overall contribution of NaV1.9. Beside the proposed general role of NaV1.7 and 1.9 in itch signalling, scrutiny of time courses suggested NaV1.8 to sustain prolonged itching. Therefore, NaV1.7 and 1.9 may represent targets in pruritus therapy.

2020.03.11 Journal club↩

Neuronal branching of sensory neurons is associated with BDNF-positive eosinophils in atopic dermatitis

Guseva D, Rüdrich U, Kotnik N, Gehring M, Patsinakidis N, Agelopoulos K, Ständer S, Homey B, Kapp A, Gibbs BF, Ponimaskin E, Raap U.

Abstract

BACKGROUND: Pruritus is a major symptom of atopic dermatitis (AD) and is transmitted by a subpopulation of non-myelinated C-type free nerve endings in the epidermis and upper dermis. Stimulation of these nerve terminals is affected by histamine, neurotrophins and physical factors. Eosinophils of patients with AD are a source of neurotrophins, including brain-derived neurotrophic factor (BDNF), levels of which correlate with disease severity.

OBJECTIVE: The purpose of this study was to determine the anatomical localization of eosinophils in the skin of patients with AD with regard to peripheral nerves and to investigate whether eosinophils induce sprouting and neurite outgrowth in murine sensory neurons.

RESULTS: Dermal axon density and the proximity of eosinophils to nerve fibres were significantly higher in AD patients vs NA. Both neuronal projections and eosinophils expressed BDNF. Furthermore, activated eosinophil supernatants induced BDNF-dependent mouse DRG neuron branching.

CONCLUSIONS AND CLINICAL RELEVANCE: Our results indicate that BDNF-positive eosinophils are also localized in close proximity with nerve fibres in AD, suggesting a functional relationship between BDNF-expressing eosinophils and neuronal projections. These observations suggest that eosinophils may have considerable impact on pruritus by supporting sensory nerve branching.

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