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.