IL-33 potentiates histaminergic itch

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 while receiving 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 after IL -33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets 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 biopsy samples 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 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 -33 receptor 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. (J Allergy Clin Immunol 2024;153:8529.)