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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
United States
Zip Code
Tomasini-Johansson, Bianca R; Mosher, Deane F (2018) Microtiter assays for quantitation of assembly of plasma and cellular fibronectin. Methods Cell Biol 143:157-170
Turton, Keren B; Wilkerson, Emily M; Hebert, Alex S et al. (2018) Expression of novel ""LOCGEF"" isoforms of ARHGEF18 in eosinophils. J Leukoc Biol 104:135-145
Bernau, Ksenija; Leet, Jonathan P; Esnault, Stephane et al. (2018) Eosinophil-degranulation products drive a proinflammatory fibroblast phenotype. J Allergy Clin Immunol 142:1360-1363.e3
Stallings, Nancy R; O'Neal, Melissa A; Hu, Jie et al. (2018) Pin1 mediates A?42-induced dendritic spine loss. Sci Signal 11:
Moon, Hyung-Geun; Kim, Seung-Jae; Jeong, Jong Jin et al. (2018) Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity 49:275-287.e5
Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J et al. (2018) Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD). J Leukoc Biol 104:69-83
Johansson, Mats W; Kelly, Elizabeth A; Nguyen, Christopher L et al. (2018) Characterization of Siglec-8 Expression on Lavage Cells after Segmental Lung Allergen Challenge. Int Arch Allergy Immunol 177:16-28
Evans, Michael D; Esnault, Stephane; Denlinger, Loren C et al. (2018) Sputum cell IL-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthmatic patients. J Allergy Clin Immunol 142:415-423
Esnault, Stephane; Hebert, Alexander S; Jarjour, Nizar N et al. (2018) Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. J Proteome Res 17:2102-2111
Bortnov, Valeriu; Annis, Douglas S; Fogerty, Frances J et al. (2018) Myeloid-derived growth factor is a resident endoplasmic reticulum protein. J Biol Chem 293:13166-13175

Showing the most recent 10 out of 106 publications