IL-33 Signaling in Sensory Neurons Promotes Dry Skin Itch

Abstract

Background

Chronic pruritus, or itch, is common and debilitating, but the neuro-immune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood.

Objectives

We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in two divergent pruritic disease models.

Methods

Plasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively.

Results

IL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology.

Conclusion

These data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight for future therapeutic strategies targeting the IL-33 pathway for chronic itch.

Key Words

• Atopic dermatitis
• chronic pruritus of unknown origin
• dry skin
• IL-33
• itch
• neuroimmunology
• pruriceptor
• pruritogen

Abbreviations:

Ab ((antibody)), AD ((atopic dermatitis)), AEW ((acetone/ether plus water)), bp ((base pair)), Cap ((Capsaicin)), CPUO ((chronic pruritus of unknown origin)), CQ ((chloroquine)), DRG ((dorsal root ganglia)), DT ((diphtheria toxin)), epidermis ((Epi)), EtOH ((ethanol)), HC ((healthy control)), His ((histamine)), i.d ((intradermal)), ILC2s ((group 2 innate lymphoid cells)), IL-33R ((IL-33 receptor)), i.p ((intraperitoneal)), KCl ((potassium chloride)), LM ((littermate)), loxP ((locus of X-over P1)), mAb ((monoclonal antibody)), MACS ((magnetic-activated cell sorting)), MasTRECK ((mast cell-specific enhancer-mediated toxin receptor-mediated conditional cell knockout)), NS ((no significance)), rh ((recombinant human)), rm ((recombinant mouse)), RNA-seq ((RNA sequencing)), stratum corneum ((SC)), Veh ((Vehicle)), WT ((wild-type))