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

Madison R Mack; Yannick Miron; Fanny Chen; Paul E Miller; Annie Zhang; Andrew Korotzer; Daniel Richman; Paul J Bryce

doi:10.3389/fnmol.2023.1258823

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

Front Mol Neurosci. 2023 Oct 5:16:1258823. doi: 10.3389/fnmol.2023.1258823. eCollection 2023.

Authors

Madison R Mack¹, Yannick Miron², Fanny Chen², Paul E Miller², Annie Zhang³, Andrew Korotzer⁴, Daniel Richman³, Paul J Bryce¹

Affiliations

¹ Immunology and Inflammation Research Therapeutic Area, Sanofi, Cambridge, MA, United States.
² AnaBios, San Diego, CA, United States.
³ Medical Affairs, Sanofi, Cambridge, MA, United States.
⁴ Medical Affairs, Regeneron Pharmaceuticals, Tarrytown, NY, United States.

Abstract

Introduction: Chronic 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.

Methods: We 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.

Results: Type 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.

Discussion: This 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.

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

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors declare that this work received funding from Sanofi. The funder was involved in the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit it for publication.