Interleukin‐4 and interleukin‐13 evoke scratching behaviour in mice

Abstract

Persistent and relapsing itch commonly manifests in inflammatory skin disorders such as atopic dermatitis (AD). AD pathogenesis is driven by interleukin‐4 (IL‐4) and interleukin‐13 (IL‐13). Dupilumab, a monoclonal antibody blocking the action of IL‐4 and IL‐13 effectively reduces the symptoms of AD and itch. Little is known whether IL‐4 and IL‐13 directly contribute to itch transduction. A recently published study (Oetjen et al, Cell, 2017, 171, 217) found IL‐4 and IL‐13 to directly activate itch‐sensory neurons in vitro. Surprisingly, they found no significant increase in scratching after intradermally injecting high doses (2.5 ug/ml) of IL‐4 and IL‐13 into mice. Similar experiments in our lab, however, suggested that both IL‐4 and IL‐13 contribute to acute itch in vivo. We intradermally injected lower doses (1 ug/ml) of IL‐4 and IL‐13 into mice and found a significant increase of scratching bouts compared to vehicle. Interestingly, the combined treatment of IL‐4 and IL‐13 produced additive increase of scratching and acute pruritus at an earlier time point compared to each cytokine administered alone. In summary, our study shows a rapid and significant increase of scratching after intradermal injection of IL‐4, IL‐13 or combined IL‐4/ IL‐13 compared to vehicle in mice 5‐10 minutes after injection. Our data suggest that IL‐4 and IL‐13 alone and combined directly act as potent acute pruritogens on sensory nerves. This finding expands our understanding of cytokines as pruritogens, how targeted anticytokine medications act in AD, and about neuroimmune communication in the skin.

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis

“…Pruritus-induced scratching is likely to enhance skin inflammation, because the severity of dermatitis is reduced by avoiding mechanical scratching by protective shields, 24 or by injecting antipruritic anti-IL-31 receptor antibody. 106,107,110 Chronic pruritus makes AD patients scratch their skin. As mentioned above, scratch injury induces CCL20 production Figure 1.…”

<p>Targeting IL-4 for the Treatment of Atopic Dermatitis</p>

“…[43][44][45][46][47] IL-4 also triggers fibroblast production of collagen, fibronectin, and fibrinogen, serving as adhesion molecules for Staphylococcus aureus. [48][49][50] Thereby, IL-4 contributes to skin barrier function impairment and to the increased susceptibility to bacterial infections. In addition, IL-4 both directly and indirectly, stimulates itch sensory neurons.…”

Advances in Understanding the Initial Steps of Pruritoceptive Itch: How the Itch Hits the Switch

“…A recent study revealed the pruritogenic effect of IL-4 and IL13R administered to mice. They were able to show an additive effect while administering IL-4 and IL13R in combination [ 222 ]. IL-4 and IL13R alone did not evoke itch response in humans, thus these findings in mice could not be recapitulated [ 223 ].…”

“…Once activated, IL13R signals through JAK1 and Tyk2 and STAT6 activation [ 229 ] ( Table 2 ). As mentioned above (see IL4R), the research on IL-4 and IL13R showed that IL13R caused scratching behavior in mice [ 222 ]. In addition, research carried out on mice suffering on IL13R induced topic dermatitis showed that additional IL13R administration stimulated TRPA1 expression, which is known for its role in pruritus [ 230 ].…”