Critical target cell-specific roles for IL-17 family cytokines/CIKS-mediated signaling in mouse models of skin and lung inflammation (CCR6P.276)

The inflammatory cytokine IL-17 has been strongly implicated in human psoriasis and in the imiquimod-induced mouse model of this disease, while the IL-17 family member IL-25 has been associated with allergic asthma in humans and with allergen-induced inflammation in mouse models. Both cytokines signal via the obligatory adaptor protein CIKS (a.k.a. Act1 or Traf3ip2). However what cells are targeted by these cytokines and to what end has not been clearly delineated in these disease contexts. We demonstrate that in imiquimod-induced psoriatic inflammation, IL-17 signals into keratinocytes to dysregulate their growth/differentiation. On the other hand, IL-17 signals into non-keratinocytes to promote cellular infiltration in this psoriasis model and to drive a positive feedback loop, resulting in increased production of IL-17. We further demonstrate that in a chronic house dust mite-induced asthma model, IL-25 uniquely contributes to generation of Th9 cells and to airway remodeling, at least in part by targeting dendritic-like cells. These findings reveal previously unappreciated, cell-type specific functions IL-17 cytokines that contribute to inflammatory diseases at barrier sites.