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The following is a summary of “IL-33 potentiates histaminergic itch,” published in the March 2024 issue of Allergy & Immunology by Trier, et al.

Itch, a prevalent symptom, can significantly impair quality of life. Histamine, a potent endogenous pruritogen, is often targeted with antihistamines as a first-line treatment for itch. However, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic even with maximal antihistamine doses. The mechanisms underlying resistance to antihistamines still need to be better understood. It was proposed that signaling the alarmin cytokine IL-33 in sensory neurons drives chronic itch by inducing neuronal sensitization to pruritogens. Thus, for a study, researchers sought to investigate if IL-33 could enhance histamine-induced (histaminergic) itch.

They evaluated itch behavior in response to histamine after administration of IL-33 or saline. Various stimuli and conditional and global knockout mice were employed to dissect cellular mechanisms. They analyzed multiple existing transcriptomic datasets, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells under basal conditions and after IL-33 stimulation, and microarrays of skin biopsy samples from individuals with CSU and healthy controls.

IL-33 augments histaminergic itch independently of IL-33 signaling in sensory neurons. Mast cells are the primary expression of the IL-33 receptor in both human and mouse skin. Upon IL-33 stimulation, mouse mast cells notably increase IL-13 levels. The enhancement of histaminergic itch by IL-33 depends on mast cell- and IL-13-mediated mechanisms. IL-33 receptor expression was elevated in the lesional skin of individuals with CSU compared to healthy controls.

The findings suggested that IL-33 signaling may be pivotal in histaminergic itch in mast cell-associated pruritic conditions such as CSU.

Reference: jacionline.org/article/S0091-6749(23)01465-3/fulltext