Background

Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic on maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined.

Objectives

Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch.

Methods

Itch behavior was assessed in response to histamine following IL-33 or saline administration. Various stimuli and conditional and global knock-out mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic datasets were evaluated, including single cell RNA-sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsies from subjects with CSU and healthy controls.

Results

IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor (IL-33R) in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell- and IL-13-dependent mechanism. IL-33R expression is increased in lesional skin of subjects with CSU compared to healthy controls.

Conclusions

Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell-associated pruritic conditions such as CSU.