Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Fanny Chen¹  Paul E. Miller¹  Yannick Miron¹  Madison R. Mack²  Paul J. Bryce²  Andrew Korotzer³  Daniel Richman⁴  Annie Zhang⁴ 

[1] AnaBios, San Diego, CA, United States;Immunology and Inflammation Research Therapeutic Area, Sanofi, Cambridge, MA, United States;Medical Affairs, Regeneron Pharmaceuticals, Tarrytown, NY, United States;Medical Affairs, Sanofi, Cambridge, MA, United States;

关键词: type 2 cytokines;    IL-4;    IL-13;    IL-33;    atopic dermatitis;    chronic itch;    sensory neurons;   

DOI  :  10.3389/fnmol.2023.1258823

 received in 2023-07-14, accepted in 2023-09-18,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionChronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system.MethodsWe measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing.ResultsType 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli.DiscussionThis study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

【 授权许可】

Unknown   
Copyright © 2023 Mack, Miron, Chen, Miller, Zhang, Korotzer, Richman and Bryce.