CEBPD Potentiates the Macrophage Inflammatory Response but CEBPD Knock-Out Macrophages Fail to Identify CEBPD-Dependent Pro-Inflammatory Transcriptional Programs

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 9; p. 2233
• Main Authors: Spek, C. Arnold, Aberson, Hella L., Butler, Joe M., de Vos, Alex F., Duitman, JanWillem
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 28.08.2021; MDPI
• Subjects: Animals; Bone marrow; CCAAT/enhancer-binding protein; CCAAT/enhancer-binding protein delta; CEBPD; Chemokines; Cloning; CRISPR; Cytokines; Datasets; Experiments; Gene expression; Inflammation; Lipopolysaccharides; LPS; macrophage; Macrophages; Plasmids; Pneumonia; Proteins; Transcription factors; Netherlands; United States > US; Switzerland; Benelux
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10092233

CCAAT/enhancer-binding protein delta (C/EBPδ) is a member of the C/EBP family of transcription factors. According to the current paradigm, C/EBPδ potentiates cytokine production and modulates macrophage function thereby enhancing the inflammatory response. Remarkably, however, C/EBPδ deficiency does not consistently lead to a reduction in Lipopolysaccharide (LPS)-induced cytokine production by macrophages. Here, we address this apparent discrepancy and show that the effect of C/EBPδ on cytokine production and macrophage function depends on both the macrophage subtype and the LPS concentration used. Using CRISPR-Cas generated macrophages in which the transactivation domain of C/EBPδ was deleted from the endogenous locus (ΔTAD macrophages), we next show that the context-dependent role of C/EBPδ in macrophage biology relies on compensatory transcriptional activity in the absence of C/EBPδ. We extend these findings by revealing a large discrepancy between transcriptional programs in C/EBPδ knock-out and C/EBPδ transactivation dead (ΔTAD) macrophages implying that compensatory mechanisms do not specifically modify C/EBPδ-dependent inflammatory responses but affect overall macrophage biology. Overall, these data imply that knock-out approaches are not suited for identifying the genuine transcriptional program regulated by C/EBPδ, and we suggest that this phenomenon applies for transcription factor families in general.