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A Critical Role for Eosinophils and CCR3 Signal Transduction in Allergic Airway Disease

Fulkerson, Patricia C.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1120337075

Abstract Details

2005, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Airway inflammation in asthma is complex, involving innate and adaptive responses, pathologic Th2 sensitization, and alterations in tolerance. In this thesis, we aimed to characterize the contribution of chemokines, CCR3 signal transduction, and eosinophils to experimental asthma. Our studies, implicating the involvement of 17 chemokines in experimental asthma, highlight the complex interaction between numerous chemokines in the setting of allergic airway inflammation. We provide evidence for a murine eosinophil inhibitory pathway mediated by the chemokine CXCL9 (Mig) that potently blocks eosinophil chemoattraction and function by a mechanism dependent on CCR3 and Rac2. Our findings support a new paradigm whereby the major eosinophil chemokine receptor CCR3, previously identified solely as a powerful activating receptor in eosinophils, can transmit positive or negative signals depending upon the ligand engaged. We also demonstrate that eosinophil recruitment into the lung tissue is dependent on CCR3 in two different chronic experimental asthma models. In addition, we provide evidence that airway eosinophilia induced by IL-13 is CCR3- and eotaxin-2-dependent. Taken together, these results establish a regulatory chemokine network with the ability to inhibit or recruit particular leukocytes and localize the cells to specific target areas within a tissue utilizing the same chemokine receptor CCR3. To further define the relationship between allergic airway inflammation and the remodeling process, we induced chronic experimental asthma in mice with eosinophil recruitment defects. We reveal a critical role for CCR3 and eosinophils in allergen-induced mucus production and the orchestration of total leukocyte recruitment into the lung lumen. Importantly, we also demonstrate that CCR3-deficiency protects against methacholine-induced airway hyperresponsiveness. In addition, analysis of the reversibility of IL-13-induced chronic inflammation and lung remodeling revealed that while some aspects of chronic airway pathology are reversible (e.g. mucus cell metaplasia and lung eosinophilia), other important features remain or worsen during the repair process, providing compelling evidence that many of the prominent effects of IL-13 in the lung remain persistent following the initial pathological insult. Collectively, we provide evidence for a central role for CCR3 signal transduction and eosinophils in the development of multiple aspects of allergic airway disease.
Marc Rothenberg (Advisor)
295 p.
Health Sciences, Immunology
eosinophil; chemokines; asthma; airway remodeling

Recommended Citations

Citations

  • Fulkerson, P. C. (2005). A Critical Role for Eosinophils and CCR3 Signal Transduction in Allergic Airway Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1120337075

    APA Style (7th edition)

  • Fulkerson, Patricia. A Critical Role for Eosinophils and CCR3 Signal Transduction in Allergic Airway Disease. 2005. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1120337075.

    MLA Style (8th edition)

  • Fulkerson, Patricia. "A Critical Role for Eosinophils and CCR3 Signal Transduction in Allergic Airway Disease." Doctoral dissertation, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1120337075

    Chicago Manual of Style (17th edition)

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© 2005, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.