Aberrant TH1 and TH17 type responses contribute broadly to perpetuating human inflammatory disease. These CD4+ T cell subpopulations mediate their effects primarily through effector cytokines including IFN-? (TH1) and IL-17, IL-17F, and IL-22 (TH17). It is the combinatorial effects of these cytokines that elicit net benefit, r detriment, to inflamed mucosal tissue. Indeed, complexity inherent in tissue integration of cytokine signaling impedes the development of improved therapeutics. Inflammatory cytokines, considered prime targets for disease intervention strategies, also perform diverse functions in wound healing, tissue regeneration and repair processes. Further research is needed to understand how we may harness inflammation-limiting and tissue- regenerating properties of these same molecules. We have uncovered a novel function for TH1/TH17 cytokines in control of the Wnt family of inflammatory mediators, including wnt5a. Wnt5a is a member of the non-canonical wnt family of glycoproteins important in organism development and immune cell function. Wnt5a controls a myriad of immune cell functions, including macrophage and lymphocyte activity at the mucosa. We will test our hypothesis that TH1/TH17 cytokines regulate mucosal wnt5a expression in-vivo. We further hypothesize that given the broad impact of wnt5a functionality, modulating wnt5a expression represents an important and novel avenue of investigation for the design of new therapeutics. In this proposal we will utilize laser-capture microdissection, a recently developed ex-vivo explant system, and surgical implantation of micro-osmotic pumps in-vivo to localize wnt5a in primary tissue and define the roles of TH1/TH17 cytokines in the reciprocal expression of wnt5a (aim1). We will also investigate the role of active and resolving inflammation on the IFN-?/IL-17/wnt5a axis in `inflammation low' (biopsy) and `inflammation high' (DSS) conditions (aim2). These studies will increase our ability to design therapeutic strategies for modulating TH1/TH17 inflammatory signaling and wnt expression in-vivo.
We previously identified a tissue protective effect of Interleukin 17 (IL-17) in modulating intestinal inflammation, confirmed by human clinical trial data; in new studies we have identified a novel mechanism of inflammatory control. IL-17 and Interferon gamma (IFN-?) differentially regulate inflammatory mediators of the Wnt family, in primary murine tissue. By defining the roles of these cytokines in regulating wnt5a and others, and investigating how active or resolving inflammation influences the IFN-?/IL-17/wnt5a axis, we expect these results will increase our ability to modulate TH1/TH17 cytokine signaling, as well as wnt5a expression, toward generating novel anti-inflammatory therapeutic strategies.