RT Journal Article
SR Electronic
T1 The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.06.442095
DO 10.1101/2021.05.06.442095
A1 Jack McCowan
A1 Phoebe M. Kirkwood
A1 Frédéric Fercoq
A1 Wouter T’Jonck
A1 Connar M. Mawer
A1 Richard Cunningham
A1 Ananda S. Mirchandani
A1 Anna Hoy
A1 Gareth-Rhys Jones
A1 Carsten G. Hansen
A1 Nik Hirani
A1 Stephen J. Jenkins
A1 Sandrine Henri
A1 Bernard Malissen
A1 Sarah R. Walmsley
A1 David H. Dockrell
A1 Philippa T. K. Saunders
A1 Leo M. Carlin
A1 Calum C. Bain
YR 2021
UL http://biorxiv.org/content/early/2021/05/06/2021.05.06.442095.abstract
AB Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against air-borne pathogens. Tissue-specific differentiation and survival of alveolar macrophages relies on niche-derived factors, such as colony stimulating factor 2 (CSF-2) and transforming growth factor beta (TGF-β). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remains poorly understood. Here, we identify that the transcriptional factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-β and CSF-2 in a PPAR-γ-dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for lipid handling, but crucial for the effective elimination of the respiratory pathogen Streptococcus pneumoniae. Finally, we show that EGR2 is required for repopulation of the alveolar niche following sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair following injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.One Sentence Summary EGR2 controls alveolar macrophage function in health and diseaseCompeting Interest StatementThe authors have declared no competing interest.