There is a fundamental gap in understanding how eosinophils (EOS) participate in inflammation and remodeling in asthmatic subjects. The lack of knowledge in this field is problematic to develop appropriate drugs to better treat a heterogenic disease such as asthma. The long-term goal is to understand the mechanisms by which EOS contribute to the development of asthma, particularly the more severe phenotypes. The objective in this Project 1 is to identify how activated EOS produce pro-inflammatory and remodeling factors that are relevant in allergic asthma. The central hypothesis is that IL-3 activates EOS to produce 1) the pro-inflammatory cytokine IL-1B and 2) the pro-fibrotic membrane protein, semaphorin7A (SEMA7A). We propose that IL-1 B drives the increase of the highly inflammatory cytokine, IL-17 in lymphocytes in the context of an allergic response. SEMA7A induces fibroblasts (Fb) differentiation toward myoFb, amplifying airway remodeling. Our preliminary data will allow us to test this hypothesis by pursuing three specific aims: 1) Determine the expression of IL-17 in the ainways after segmental allergen challenge in patients with asthma. Measure IL-1B release from blood and ainway EOS, and connect the release of IL-1B with IL-17 expression in vivo and with EOS ability to increase IL-17 by CD4+ T lymphocytes in vitro. 2) Define the mechanisms responsible for IL-3-induced IL-1B. The mechanisms analyzed include mRNA stability and IL-1B maturation through the inflammasome. 3) Analyze the expression and regulation of SEMA7A on blood and ainway EOS and determine the effect of SEMA7A on human bronchial Fb. The approach is innovative addressing new functions attributed to EOS. The release of bioactive IL-1B by EOS, as well as the expression of SEMA7A on EOS, are both novel. The implication of EOS in IL-17 production has never been shown and the function of SEMA7A on human Fb is unknown. These mechanisms will be analyzed in IL-3-activated EOS in vitro or in vivo in the context of a segmental allergen challenge. This latter in vivo approach, which mimics natural allergic asthma, arguably sets our group apart in our abilities to analyze airway EOS in humans. The proposed research is significant because it is expected to advance our understanding ofthe role of EOS in asthma, and of EOS potential function in the development of severe asthma. Ultimately, the knowledge acquired by these studies, will help to define new potential targets for drugs in needs for patients refractory to current treatments.
We propose that IL-3 contributes to eosinophil function in asthma by 1) influencing CD4+ T cell production of the pro-inflammatory cytokine IL-17, and 2) inducing expression ofthe profibrotic molecule semaphorin 7 A. The focus on IL-3 is a paradigm shift from current IL-5-targeted therapies. Understanding the cellular and biomolecular mechanisms down-stream of eosinophil activation by IL-3 will reveal novel pathways with therapeutic implications in asthma and other eosinophils-related diseases.
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