Clinical and experimental investigations have demonstrated a strong correlation between Th2 cells, eosinophils and allergic lung disease severity suggesting an integral role for both of these cells in asthma. Th2 cells induce asthma through the secretion of cytokines (IL-4 and IL-13) that activate inflammatory and effector pathways. The ability of IL-13 blockade to abrogate critical aspects of experimental asthma has led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. In particular, CCR3 and its ligands have emerged as central regulators of eosinophils during asthmatic responses. We have established that IL-13 induces CCR3 activating ligands (e.g. the eotaxins), and in conjunction with IL-5, these chemokines induce lung eosinophilia, which in turn amplifies IL-13 production and IL-13-associated lung pathology including eosinophil-mediated lung remodeling (e.g. goblet cell metaplasia). We have also demonstrated a critical role for IL-13 receptor ?1 (IL-13R??1), the type 2 IL-4R, in promoting the cardinal features of asthma (AHR and mucus production). In OVA and IL-4-induced models of experimental asthma, airway eosinophilia, however, developed in the absence of IL-13R??1 suggesting that eosinophilia depends more on IL-4 than IL-13 at least under these experimental conditions. This implicates the type 1 IL-4R in the induction of eosinophilia because IL-4, unlike IL-13, signals through the type 1 as well as the type 2 IL-4R. These preliminary observations need to be further elucidated as they imply that IL-13 blockade in asthma patients could result in sustained lung eosinophilia. In this regard, we are focusing on identifying alternative pathways and regulatory mechanisms involved in the development of IL-13-associated lung eosinophilia. Notably, we have recently demonstrated that the cytokine Relm-? is induced by IL-4 and IL-13 by an IL-13R?1-independent pathway in the OVA model and that Relm-?? displays eosinophil chemoattractant activity. Furthermore, we have begun to characterize IL-13-induced microRNAs (miR) that may regulate allergic lung responses including eosinophilia. The central hypothesis of this application is that allergen-induced lung eosinophil responses are differentially regulated by the type 1 and type 2 IL-4R and by Relm-? and miR-21.
In Aim 1, we will examine alternative pathways for eosinophil recruitment to the lung. The central hypothesis of this aim is that eosinophil recruitment to the lung is mediated by distinct mechanisms involving type 1 and type 2 IL-4R pathways.
In Aim 2, we will examine the involvement of Relm-? in lung eosinophilia and other IL-13-driven responses. We will test the hypothesis that the Relm-? contributes to the effects of allergen, IL-4 and IL-13 on allergic lung disease and does this, at least in part, by regulating eosinophil accumulation.
In Aim 3, we will examine the regulation of eosinophil development and activation by IL-13. We will test the hypothesis that eosinophil activation and/or development are stimulated by a combination of (1) IL-13 directly, (2) by Relm-? and (3) by miR-21.
The proposed aims should uncover mechanisms by which chemokines, eosinophils, and IL-13 cooperate in the induction of experimental asthma. By examining how IL-13 and chemokines interact with eosinophils and focusing on miRNA regulation of gene expression and a recently identified Th2-associated molecule (Relm-?), we hope to broaden our understanding of asthma-associated lung pathology. These results will provide a fundamental basis for understanding the potential utility of the immune-based therapeutics (e.g. anti-cytokines agents) that are currently being developed for the treatment of asthma;thus, helping to clarify the unique and comparative effects of interrupting IL-4, IL-13 and/or their receptors in asthma.
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