Role of Ezrin in Macrophages

PROJECT SUMMARY
Macrophages (MΦs) 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 MΦs (TR-MΦs) are the
interstitial and alveolar MΦs, which have complementary but distinct functions. In response to infections, lungs
are rapidly populated by waves of Ly6C+ circulating monocytes. In concert with TR-MΦs, these monocytes fight
the infection, then facilitate the resolution of the inflammatory response. Many chronic lung inflammatory
diseases, including cystic fibrosis (CF), are associated with dysregulated MΦ function. Our long- term goal is to
understand how different lung MΦ 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/MΦ function. Our central hypothesis is that ezrin controls monocyte/MΦ cortical actin
organization and signal transduction events in response to inflammatory/infectious stimuli. These cellular
changes allow the MΦs 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 MΦs from patients with CF (our 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 MΦ
functions, we could identify potential therapeutic targets for lung diseases. Our specific aims will test the following
hypotheses: (Aim 1) ezrin is required for the signaling that drives MΦs to adhere to the lung extracellular matrix
and to differentiate in response to LPS; (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) the acquired “cellular ezrin low-state” inactivated CF MΦs is central to their uncontrolled immune
signaling and reduced phagocytosis. The contribution is significant since very little is known about ezrin’s role in
regulating lung MΦ activation. Our proposed research is innovative because we will use an unprecedented
mouse model in which ezrin is knocked out in monocytes and MΦs. Thus, the proposed studies will investigate in
depth the consequences of ezrin loss in monocytes and MΦs during lung infection and inflammation.

Grant Number: 5R01AI153422-05
NIH Institute/Center: NIH
Principal Investigator: Emanuela Bruscia