Concluding remarks and future perspectives
Although the biological function of IL-31 has predominantly been associated with AD and pruritus, it is now clear that IL-31 is more than an ‘itchy’ cytokine. The importance of IL31RA in AD pathophysiology was demonstrated by early and recent trials validating a marked reduction in itch along with improvement of eczema, in some studies, in AD patients using anti-IL31RA antibody.72,74,80 The success of these trials in moderate to severe AD suggests that sole blockage of the IL-31 pathway may be sufficient to achieve an acceptable therapeutic outcome in some patients. However, the success of the IL-4Rα-inhibiting antibody dupilumab in AD patients demands further evaluation how to stratify the heterogenous population of AD patients for the best ‘personalized’ benefit. More large-scale, long-term studies will help to understand benefit of IL-31-axis inhibition on AD onset, progression and resolution, as well as its impact beside pruritus on inflammation (eczema) and barrier dysregulation. A recent trial of nemolizumab in prurigo nodularis patients suggests the applicability of anti-IL31/IL31RA biologicals as therapeutics of certain pruritic diseases.96 For example, in cancer-associated itch the IL-31 axis might be recognized as a valid treatment target, considering the growth-promoting capacity of IL-31 signaling in various cell types.37,52,97 The efficacy of the IL-31-axis inhibition in different types of itch will be important to understand in order to further develop and enhance our therapeutic ‘toolbox’ for the treatment of currently therapy-refractory pruritic diseases.
Il-31 triggers regulatory responses in epithelial cells of all mucosal sites, namely skin, lung and the GI tract. However, while we begin to understand the cutaneous function of IL-31, its effect on intestinal and pulmonary cell populations is less clear. The involvement of IL-31 in inflammatory disorders of the GI tract or lung is at this stage preliminary and far from being understood. IL-31 likely acts in both tissues in a similar fashion as observed in skin, nurturing inflammatory responses of resident cells and cross-communicating as a regulatory signal to receptive T cells, DC subsets and probably nerves. However, to fully understand the IL-31-axis in gut, lung and skin during homeostasis and inflammatory conditions, an array of in vitro , ex vivoand in vivo studies will need to be performed.
Deciphering the precise IL-31-induced mechanisms in organ- and disease models, will probably lead to new therapeutic options for the treatment of skin diseases, as well as atopic disorders (nasal polyposis), or disorders in the lung or gastrointestinal tract. However, as mentioned above, because IL-31 itself has a dual inflammatory effect depending on disease stage, the beneficial role of neutralizing the IL-31 pathway needs to be explored for each disease.