Since the discovery of its very first member in 1974, the IL-1 family has expanded into a group of 11 potent molecules which are essential in both innate and acquired immunity. Pro-inflammatory cytokines IL-36α, IL-36β, and IL-36γ and their receptor antagonists IL-36Ra and IL-38, which belong to the IL-36 subfamily, are some of the most recently identified members. Recent studies show that these members possess pro-inflammatory and anti-inflammatory activities and may take part in the pathogenesis of allergy. In this review, the involvement and importance of these newly described IL-1 family members in the most common allergic diseases, i.e., atopic dermatitis (AD), allergic asthma, and allergic rhinitis, will be discussed.
Dysregulation of IL-36 and IL-38 was observed in the skin and respiratory tract of AD, allergic rhinitis, and allergic asthma individuals. Although the upregulation in IL-36α and IL-36γ observed in the lesional skin of AD patients was unexpectedly small, IL-36 may play an important role in AD pathogenesis especially upon Staphylococcus aureus colonization. While IL-36γ regulates eosinophils to induce an inflammatory response in allergic rhinitis, IL-36α was found to regulate Th17 immunity. IL-36 receptor antagonists, IL-36Ra and IL-38, however, both show promising anti-inflammatory activities against allergic asthma. Of note, IL-38 in allergic asthmatic children is significantly lower than their healthy counterparts, while the anti-inflammatory effects of IL-38 in allergic asthma exacerbation upon viral-like infection were demonstrated in in vitro, HDM-induced, and humanized mice models. Dysregulated expression of IL-36 and IL-38 observed in allergic patients and mice models revealed that they may have essential roles in the pathogenesis in AD, allergic rhinitis, and allergic asthma, especially during the host defense against pathogens at inflammatory sites. Their receptor antagonists, IL-36Ra and IL-38, could also be promising biologics in the control of allergy. Since allergic diseases are phenotypically complex, contradictory data obtained in different studies may be explained if further stratification of disease endotypes is explored. Genetically modified mice model and investigation in anti-IL-36 treatment may be useful to characterize the therapeutic potential of these cytokines in the regulation of allergy in the future.

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