KLF Family Members Control Expression of Genes Required for Tissue Macrophage Identities

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2025 Mar 12

PMID 40072341

Authors

Kathleen Pestal

Leianna C Slayden

Gregory M Barton

Affiliations

Soon will be listed here.

Abstract

Tissue-resident macrophages adopt distinct gene expression profiles and exhibit functional specialization based on their tissue of residence. Recent studies have begun to define the signals and transcription factors that induce these identities. Here we describe an unexpected and specific role for the broadly expressed transcription factor Krüppel-like factor 2 (KLF2) in the development of embryonically derived large cavity macrophages (LCMs) in the serous cavities. KLF2 not only directly regulates the transcription of genes previously shown to specify LCM identity, such as retinoic acid receptors and GATA6, but also is required for induction of many other transcripts that define the identity of these cells. Our results suggest that KLF4 may similarly regulate the identity of alveolar macrophages in the lung. These data demonstrate that broadly expressed transcription factors, such as group 2 KLFs, can play important roles in the specification of distinct identities of tissue-resident macrophages.

References

Chakraborty S, Singh A, Wang L, Wang X, Sanborn M, Ye Z . Trained immunity of alveolar macrophages enhances injury resolution via KLF4-MERTK-mediated efferocytosis. J Exp Med. 2023; 220(11). PMC: 10450795. DOI: 10.1084/jem.20221388. View

Skene P, Henikoff S . An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife. 2017; 6. PMC: 5310842. DOI: 10.7554/eLife.21856. View

Han J, Gallerand A, Erlich E, Helmink B, Mair I, Li X . Human serous cavity macrophages and dendritic cells possess counterparts in the mouse with a distinct distribution between species. Nat Immunol. 2023; 25(1):155-165. PMC: 10990619. DOI: 10.1038/s41590-023-01688-7. View

Ahmad N, Lingrel J . Kruppel-like factor 2 transcriptional regulation involves heterogeneous nuclear ribonucleoproteins and acetyltransferases. Biochemistry. 2005; 44(16):6276-85. DOI: 10.1021/bi050018s. View

Rauschmeier R, Gustafsson C, Reinhardt A, A-Gonzalez N, Tortola L, Cansever D . Bhlhe40 and Bhlhe41 transcription factors regulate alveolar macrophage self-renewal and identity. EMBO J. 2019; 38(19):e101233. PMC: 6769426. DOI: 10.15252/embj.2018101233. View

Dorr D, Obermayer B, Weiner J, Zimmermann K, Anania C, Wagner L . C/EBPβ regulates lipid metabolism and isoform 2 expression in alveolar macrophages. Sci Immunol. 2022; 7(75):eabj0140. DOI: 10.1126/sciimmunol.abj0140. View

Kim K, Williams J, Wang Y, Ivanov S, Gilfillan S, Colonna M . MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J Exp Med. 2016; 213(10):1951-9. PMC: 5030807. DOI: 10.1084/jem.20160486. View

Villarreal Jr G, Zhang Y, Larman H, Gracia-Sancho J, Koo A, Garcia-Cardena G . Defining the regulation of KLF4 expression and its downstream transcriptional targets in vascular endothelial cells. Biochem Biophys Res Commun. 2009; 391(1):984-9. PMC: 4165389. DOI: 10.1016/j.bbrc.2009.12.002. View

Okabe Y, Medzhitov R . Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell. 2014; 157(4):832-44. PMC: 4137874. DOI: 10.1016/j.cell.2014.04.016. View

10.

Herta T, Bhattacharyya A, Rosolowski M, Conrad C, Gurtner C, Gruber A . Krueppel-Like Factor 4 Expression in Phagocytes Regulates Early Inflammatory Response and Disease Severity in Pneumococcal Pneumonia. Front Immunol. 2021; 12:726135. PMC: 8473698. DOI: 10.3389/fimmu.2021.726135. View

11.

Finlay C, Parkinson J, Zhang L, Chan B, Ajendra J, Chenery A . T helper 2 cells control monocyte to tissue-resident macrophage differentiation during nematode infection of the pleural cavity. Immunity. 2023; 56(5):1064-1081.e10. PMC: 7616141. DOI: 10.1016/j.immuni.2023.02.016. View

12.

Schneider C, Nobs S, Kurrer M, Rehrauer H, Thiele C, Kopf M . Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014; 15(11):1026-37. DOI: 10.1038/ni.3005. View

13.

Picelli S, Faridani O, Bjorklund A, Winberg G, Sagasser S, Sandberg R . Full-length RNA-seq from single cells using Smart-seq2. Nat Protoc. 2014; 9(1):171-81. DOI: 10.1038/nprot.2014.006. View

14.

Weinreich M, Takada K, Skon C, Reiner S, Jameson S, Hogquist K . KLF2 transcription-factor deficiency in T cells results in unrestrained cytokine production and upregulation of bystander chemokine receptors. Immunity. 2009; 31(1):122-30. PMC: 2724594. DOI: 10.1016/j.immuni.2009.05.011. View

15.

Das H, Kumar A, Lin Z, Patino W, Hwang P, Feinberg M . Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci U S A. 2006; 103(17):6653-8. PMC: 1458936. DOI: 10.1073/pnas.0508235103. View

16.

Gosselin D, Link V, Romanoski C, Fonseca G, Eichenfield D, Spann N . Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell. 2014; 159(6):1327-40. PMC: 4364385. DOI: 10.1016/j.cell.2014.11.023. View

17.

Sakai M, Troutman T, Seidman J, Ouyang Z, Spann N, Abe Y . Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Immunity. 2019; 51(4):655-670.e8. PMC: 6800814. DOI: 10.1016/j.immuni.2019.09.002. View

18.

Nguyen H, Tran B, Muller W, Jack R . IL-10 acts as a developmental switch guiding monocyte differentiation to macrophages during a murine peritoneal infection. J Immunol. 2012; 189(6):3112-20. DOI: 10.4049/jimmunol.1200360. View

19.

Meers M, Tenenbaum D, Henikoff S . Peak calling by Sparse Enrichment Analysis for CUT&RUN chromatin profiling. Epigenetics Chromatin. 2019; 12(1):42. PMC: 6624997. DOI: 10.1186/s13072-019-0287-4. View

20.

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View