Ezrin drives adaptation of monocytes to the inflamed lung microenvironment.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B829
Abstract ID: 5418

Presenting Author:
Ravindra Gudneppanavar , Postdoctoral Associate at Yale Sch. of Med.

Abstract:

We have previously shown that the actin-binding protein ezrin is reduced and displaced from the plasma membrane in monocytes/macrophages (MΦs) from patients with cystic fibrosis (CF) and CF mice, impacting immune response to bacteria. However, its role in monocyte/MΦ is not fully understood. To investigate how the lack of ezrin affects monocyte/MΦ functions in response to lung infections, we developed a monocyte/MΦ-specific ezrin knock out mouse model (Ez-KO^m) . We aerosolized  WT and Ez-KO^m mice with LPS and assessed the number of lung monocyte/MΦ by  flow cytometry and their transcriptional profile via RNA-seq, followed by in vitro functional studies. In WT mice, ezrin is induced by LPS in all lung monocyte/MΦ populations, with the highest induction observed in the interstitial MΦs (IMs) (4-fold higher than monocytes). LPS treated Ez-KO^m mice exhibit a significant reduction in IM numbers compared with WT and increased expression of pro-inflammatory markers (Il6, Tnfα, and Cxcl1). RNA-seq revealed differentially expressed genes in Ez-KO^m monocytes/IMs related to adhesion, proliferation and cytoskeleton rearrangement. Consistently, Ez-KO^m monocytes treated in vitro with LPS on collagen show stunted filopodia, altered F-actin distribution, reduced adhesion and increased cell death due to defective FAK and PI3K/AKT signaling. Our studies suggest that ezrin plays a critical role in the survival and adaptation of monocytes to the lung extracellular matrix during infections.