Propionate alleviates itch in murine models of atopic dermatitis by modulating sensory TRP channels of dorsal root ganglion

• Published in: Allergy (Copenhagen) Vol. 79; no. 5; pp. 1271 - 1290
• Main Authors: Xu, Yao, Qiu, Zhuoqiong, Gu, Chaoying, Yu, Su, Wang, Shangshang, Li, Changlin, Yao, Xu, Li, Wei
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.05.2024
• Subjects: Animal models; Animals; Atopic dermatitis; Calcitonin; Calcitonin Gene-Related Peptide - metabolism; calcitonin gene‐related peptide; Calcium imaging; Capsaicin; Dermatitis; Dermatitis, Atopic - drug therapy; Dermatitis, Atopic - metabolism; Disease Models, Animal; Dorsal root ganglia; dorsal root ganglion; Electrophysiology; Excitability; Ganglia, Spinal - metabolism; HEK293 Cells; Humans; itch; Male; Mice; Microbiomes; Molecular Docking Simulation; Nerves; propionate; Propionates - pharmacology; Propionates - therapeutic use; Propionic acid; Pruritus; Pruritus - drug therapy; Pruritus - etiology; Pruritus - metabolism; Quality of life; Sensory neurons; Sensory Receptor Cells - metabolism; Skin; skin microbiome metabolite; Transient Receptor Potential Channels - metabolism; TRP channels; itch; calcitonin gene‐related peptide; dorsal root ganglion; atopic dermatitis; skin microbiome metabolite; TRP channels; propionate
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.15998

Background Itch is the most common symptom of atopic dermatitis (AD) and significantly decreases the quality of life. Skin microbiome is involved in AD pathogenesis, whereas its role in the regulation of itch remains elusive. In this study, we aimed to investigate the effects of skin microbial metabolite propionate on acute and chronic pruritus and to explore the mechanism. Methods Using various mouse models of itch, the roles of propionate were explored by behavioral tests and histopathology/immunofluorescent analysis. Primary‐cultured dorsal root ganglion neurons and HEK293 cells expressing recombinant human TRP channels were utilized for in vitro calcium imaging/in vivo miniature two‐photon imaging in combination with electrophysiology and molecular docking approaches for investigation of the mechanism. Results Propionate significantly alleviated itch and alloknesis in various mouse models of pruritus and AD and decreased the density of intraepidermal nerve fibers. Propionate reduced the responsiveness of dorsal root ganglion neurons to pruritogens in vitro, attenuated the hyper‐excitability in sensory neurons in MC903‐induced AD model, and inhibited capsaicin‐evoked hTRPV1 currents (IC50 = 20.08 ± 1.11 μM) via interacting with the vanilloid binding site. Propionate also decreased the secretion of calcitonin gene‐related peptide by nerves in MC903‐induced AD mouse model, which further attenuated itch and skin inflammation. Conclusion Our study revealed a protective effect of propionate against persistent itch through direct modulation of sensory TRP channels and neuropeptide production in neurons. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD. Skin microbial metabolite propionate alleviates itch and skin inflammation. Propionate reduces the responsiveness of DRG neurons to pruritogens, directly modulates sensory TRP channels, and inhibits the secretion of neuropeptide CGRP. Regulation of itch via the skin microbiome might be a novel strategy for the treatment of AD.Abbreviations: AD, atopic dermatitis; AEW, acetone‐ether‐water; CGRP, calcitonin gene‐related peptide; DRG, dorsal root ganglion; GPR41, G protein‐coupled receptor 41; HEK293, human embryonic kidney cell line; KD, knockdown; MC903, calcipotriol; SCFAs, short chain fatty acids; Th2, T helper 2 cell; TRPV1, transient receptor potential vanilloid 1; WT, wild type.