IL-4, IL-13 cause scratching in mice

A recent study¹ demonstrated an increased scratching behavior in mice soon after being treated intradermally with interleukin-4 (IL-4) and interleukin-13 (IL-13), supporting the pruritic effects of these two cytokines and further, underscoring the benefit of pharmacologic agents that target these cytokines currently being used in conditions associated with pruritus such as atopic dermatitis.

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Driven by IL-4 and IL-13, atopic dermatitis is an inflammatory skin disease that is known to be associated with persistent relapsing pruritus. Pharmacologic therapies that target the action of IL-4 and IL-13, such as the human anti-IL-4 receptor alpha (IL-4Rα) monoclonal antibody dupilumab recently approved for the treatment of moderate-to-severe atopic dermatitis, are currently being used to address the neuroimmune dysfunction and help quell the intense symptoms of atopic dermatitis and itch. Whether IL-4 and IL-13 are directly involved in itch transduction remains a gray area.

Researchers from the Charles Institute of Dermatology, University College Dublin, Ireland, and the Department of Dermatology and Venereology, Hamad Medical Corporation, Doha, Qatar, recently collaborated on a study that investigated the pruritic effects of intradermally injected IL-4 and IL-13 in wild-type mice. In the study, 10ul of recombinant mouse IL-4 (1μg), IL-13 (1μg) alone or in combination, histamine (50μg) or vehicle (0.1% BSA in PBS) were intradermally injected, into the right cheek of a cohort of wild-type mice. Video recordings of the mice were made immediately after injection for 30 minutes and scratching behavior was observed and measured.

Compared to vehicle, results showed that there was a significant increase in scratching bouts after 5-10 minutes and an overall significant effect of treatment in mice injected with IL-4. In similar, IL-13 injected mice also demonstrated a significant increase in scratching compared to vehicle. Data also showed that compared to vehicle, there was a significant increase in scratching after the combination administration of both IL-4 and IL-13. Of note, the combination treatment showed to elicit acute pruritus at an earlier time point than the two treatments administered alone.

“Our results show that IL-4 and IL-13 produce a direct, acute pruritic effect immediately after intradermal injection in mice. Our data show comparable direct effects of IL-4 and IL-13, as observed for IL-31 which is considered as a direct acute pruritogen in mice,” writes Martin Steinhoff, M.D., Ph.D., and colleagues, in the study recently published in Experimental Dermatology.

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Nevertheless, the researchers said that it remains to be seen in future studies whether IL-4 and IL-13 can elicit the acute pruritic effects in humans in clear distinction to the pruritic effects of IL-31, which acts as an acute pruritogen in mice and a late onset pruritogen in humans.

The current study data suggest that IL-4 and IL-13 alone and combined directly act as potent, acute (immediate) pruritogens on sensory nerves. According to the researchers, these findings can help expand upon the understanding of cytokines as pruritogens, how targeted anticytokine medications act in atopic dermatitis, and about neuroimmune communication in the skin.

“Clarifying the role of cytokines directly on nerves is important to better understand their role in human disease and to interpret the effects of anticytokine therapies with respect to blocking inflammation and/or pruritus, respectively,” the researchers say. 

References:

1. Campion M, Smith L, Gatault S, Metais C, Buddenkotte J, Steinhoff M. Interleukin-4 and interleukin-13 evoke scratching behavior in mice. Exp Dermatol. 2019 Sep 10. doi: 10.1111/exd. 14034. [Epub ahead of print]