The Role of New IL-1 Family Members (IL-36 and IL-38) in Atopic Dermatitis, Allergic Asthma, and Allergic Rhinitis.

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.