Macrophages (M?s) kill microorganisms, engulf dead cells and debris, and regulate the immune response. They are thus gatekeepers of tissue health, including the lungs. The lung-tissue-resident M?s (TR-M?s) are the interstitial and alveolar M?s, which have complementary but distinct functions. In response to infections, lungs are rapidly populated by waves of Ly6C+ circulating monocytes. In concert with TR-M?s, these monocytes fight the infection, then facilitate resolution of the inflammatory response. Many chronic lung inflammatory diseases, including cystic fibrosis (CF), are associated with dysregulated M? function. Our long- term goal is to understand how different lung M? populations contribute to lung hyper-inflammation and infection, and to elucidate the biology of these distinct cell populations. The objective of this proposal is to characterize ezrin?s role in monocyte/M? function. Our central hypothesis is that ezrin controls monocyte/M? cortical actin organization and signal transduction events in response to inflammatory/infectious stimuli. These cellular changes allow the M?s to spread, move, phagocytize, and survive, thus shaping the magnitude and quality of the lung immune response to infections. The rationale for these studies is that low ezrin levels have been found in M?s from patients with CF (our own work). Other investigators have also reported low ezrin levels in blood cells from individuals with asthma. Thus, by elucidating the molecular mechanism by which ezrin shapes lung M? functions, we could identify potential therapeutic targets for lung diseases.
Our specific aims will test the following hypotheses:
(Aim 1) ezrin is necessary for monocyte/M? adaptation to the inflamed lung microenvironment;
(Aim 2) ezrin is needed for efficient phagocytosis of Staphylococcus aureus and Pseudomonas aeruginosa, two microorganisms that CF patients fail to efficiently eradicate from their lungs;
(Aim 3) functional CFTR, the gene that causes CF when mutated, is needed to preserve normal ezrin levels during M? activation. The contribution is significant since very little is known about ezrin?s role in regulating lung M? activation. Our proposed research is innovative because we will use an unprecedented mouse model in which ezrin is knocked out specifically in monocytes and M?s. Thus, the proposed studies will investigate in depth the consequences of ezrin loss in monocytes and M?s during lung infection and inflammation.

Public Health Relevance

Our proposed studies will investigate how ezrin, an actin binding protein, regulates the macrophage immunomodulatory and bactericidal functions during lung infections. The relevance of this study is based on our recent finding that ezrin levels are low in macrophages from individuals with cystic fibrosis, a disease characterized by lung infection and hyper-inflammation. These studies will deepen understanding of M? biology and identify potential targets for therapies against lung infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Innate Immunity and Inflammation Study Section (III)
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Davidson, Wendy F
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Yale University
Schools of Medicine
New Haven
United States
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