The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair
McCowan, J. et al. (BioRxiv) DOI: 10.1101/2021.05.06.442095
The local environmental signals and molecular pathways that control the tissue-specific imprinting of macrophages remain largely unexplored. In this preprint, McCowan et al. discovered that the transcriptional factor EGR2 is indispensable for the tissue-specific differentiation and immunological functions of alveolar macrophages. The authors identified EGR2 expression to be unique and evolutionary conserved in alveolar macrophages, and showed that EGR2 is a required regulator of the tissue-specific transcriptional programme of alveolar macrophages. Mechanistically, the authors show that EGR2 is driven by TGF-β and CSF-2 in a PPAR-γ-dependent manner which further induces C/EBPβexpression, and is selectively induced in alveolar macrophages during alveolarization in neonatal period. Regarding the functions of EGR2, the authors found the transcription factor to be crucial for effective control of the respiratory pathogen Streptococcus pneumoniae. Finally, they demonstrated that the maintenance of pulmonary tissue homeostasis after injury relies on monocyte-derived macrophages in an EGR-dependent manner, implying that EGR2 plays an important role on the repopulation of the alveolar macrophage niche.
This preprint gives a thorough and detailed analysis of how EGR2 controls alveolar macrophage differentiation by giving a complete picture on the mechanism and functions of EGR2.
However, important and interesting questions remain open. In terms of the regulation of EGR2 expression, it would be interesting to further study how TGF-β and CSF-2 cooperate to drive EGR2 expression, what is the downstream pathway for EGR2 to further control macrophage differentiation, and why this pathway is specifically activated in alveolar macrophages.
Also, it would be very informative to further investigate the relationship between different interesting findings in this preprint, including the relationship between alveolar macrophage differentiation control and the immunological functions of EGR2, the relationship between pathogen control and alveolar macrophage repopulation.
This preprint addresses the discrepancies in the literature regarding the role of EGR2 in macrophage differentiation regulation and the regulation of EGR2 expression, probably resulting from the limitations of in vitro systems employed by previous studies, as global EGR2 knockout is lethal in mice. In this study, McCowan et al. generated a strain in which only myeloid cells lack EGR2 in a constitutive manner, and thoroughly characterised the functions and regulations of EGR2 in vivo. Previously, EGR2 had been shown to be redundant in macrophage differentiation and IL-4 was long-believed to be crucial in the upregulation of EGR2 expression. Using this in vivo model, the authors proved the indispensable role of EGR2 in macrophage differentiation and that IL-4 is not necessary for inducing EGR2 expression in vivo.
Understanding how tissue-specific macrophages are differentiated yields important insights into the causes of many diseases resulting from abnormal functions of tissue-specific macrophages. Deciphering the mechanism governing alveolar macrophage differentiation is crucial for understanding many lung pathologies, including severe COVID-19.
Reviewed by Wanlin He as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.