Kolostyák, Zsuzsanna and Bojcsuk, Dóra and Baksa, Viktoria and Máthéné Szigeti, Zsuzsa and Bene, Krisztián and Czimmerer, Zsolt and Botó, Pál and Fadel, Lina and Póliska, Szilárd and Halasz, Laszlo and Tzerpos, Petros and Berger, Wilhelm K. and Villabona-Rueda, Andres and Varga, Zsófia and Kovács, Tünde and Patsalos, Andreas and Pap, Attila and Vámosi, György and Bay, Péter and Dezső, Balázs and Spite, Matthew and D'Alessio, Franco R. and Szatmári, István and Nagy, László (2024) EGR2 is an epigenomic regulator of phagocytosis and antifungal immunity in alveolar macrophages. JCI INSIGHT, 9 (17). No. e164009. ISSN 2379-3708
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Abstract
Alveolar macrophages (AMs) act as gatekeepers of the lung's immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) Early Growth Response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA-sequencing, ATAC-sequencing, and CUT&RUN). The predicted direct proximal targets of EGR2 included a subset of AM identity genes, and ones related to pathogen recognition, phagosome maturation, and adhesion, such as Clec7a, Atp6v0d2, Itgb2, Rhoc, and Tmsb10. We provided evidence that EGR2 deficiency led to impaired zymosan internalization and reduced the capacity to respond to Aspergillus fumigatus. Mechanistically, the lack of EGR2 altered the transcriptional response, secreted cytokines (i.e., CXCL11), and inflammation-resolving lipid mediators (i.e., RvE1) of AMs during in vivo zymosan-induced inflammation, which manifested in impaired resolution. Our findings demonstrated that EGR2 is a key proximal transcriptional activator and epigenomic bookmarker in AMs responsible for select, distinct components of cell identity and a protective transcriptional and epigenomic program against fungi.
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| Additional Information: | Funding Agency and Grant Number: National Research, Development and Innovation Fund of Hunga-ry [TKP2021-EGA]; Hungarian Scientific Research Fund [OTKA NN129371, ANN135107]; New National Excellence Program of the Ministry for Innovation and Technology [NKP-22-5 - SZTE-549]; Jnos Bolyai Research Scholarship of the Hungarian Academy of Sciences [BO/00594/22/8] Funding text: The authors would like to thank Timea Silye-Cseh, Marta Beladi, and Aniko Kerekgyartone Nagy technical assistance and members of the Nagy laboratory for discussions. LN has been supported grants from the NIH (DK115924, DK124782, HL170426). The Nuclear Hormone Receptor Laboratory supported by the Hungarian Scientific Research Fund KKP129909 and K147147, and DB was supported by the Hungarian Scientific Research Fund (OTKA PD137902). The work of P Bai was supported grants from the National Research, Development and Innovation Office (K123975, TKP2021-EGA-19, TKP2021-EGA-20). The projects TKP2021-EGA-19 and TKP2021-EGA-20 have been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme. GV is supported by the Hungarian Scientific Research Fund (OTKA NN129371 and ANN135107). ZC is supported by the New National Excellence Program of the Ministry for Innovation and Technology (UNKP-22-5 - SZTE-549) and by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences BO/00594/22/8.r with the support provided from the National Research, Development and Innovation Fund of Hunga-ry, financed under the TKP2021-EGA funding scheme. GV is supported by the Hungarian Scientific Research Fund (OTKA NN129371 and ANN135107) . ZC is supported by the New National Excellence Program of the Ministry for Innovation and Technology (& Uacute;NKP-22-5 - SZTE-549) and by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences BO/00594/22/8. |
| Uncontrolled Keywords: | Inflammation; TRANSCRIPTION; innate immunity; infectious disease; Fungal infections |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 14 Apr 2025 08:49 |
| Last Modified: | 14 Apr 2025 08:49 |
| URI: | https://real.mtak.hu/id/eprint/217743 |
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