title: Kruppel-like Factor 6 Promotes Macrophage-mediated Inflammation by Suppressing B Cell Leukemia/Lymphoma 6 Expression.
abstract: Macrophages are the predominant innate immune cells recruited to tissues following injury or infection. These early-responding, pro-inflammatory macrophages play an essential role in the amplification of inflammation. However, macrophage pro-inflammatory gene expression should be tightly regulated to avert host tissue damage. In this study, we identify the Kruppel-like transcription factor 6 (KLF6)-B cell leukemia/lymphoma 6 (BCL6) signaling axis as a novel regulator of macrophage inflammatory gene expression and function. Utilizing complementary gain- and loss-of-function studies, we observed that KLF6 is essential for macrophage motility under ex vivo and in vivo conditions. Concordant with these observations, myeloid-specific deficiency of KLF6 significantly attenuates macrophage pro-inflammatory gene expression, recruitment, and progression of inflammation. At the molecular level, KLF6 suppresses BCL6 mRNA and protein expression by elevating PR domain-containing 1 with ZNF domain (PRDM1) levels in macrophages. Interestingly, pharmacological or genetic inhibition of BCL6 in KLF6-deficient macrophages completely abrogated the attenuation of pro-inflammatory cytokine/chemokine expression and cellular motility. Collectively, our observations reveal that KLF6 repress BCL6 to enhance macrophage inflammatory gene expression and function.
authors.affiliation: From the Departments of Medicine.
authors.forename: Gun-Dong
authors.initials: GD
authors.lastname: Kim
authors.affiliation: the Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, and.
authors.forename: Riku
authors.initials: R
authors.lastname: Das
authors.affiliation: From the Departments of Medicine.
authors.forename: Lediana
authors.initials: L
authors.lastname: Goduni
authors.affiliation: the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201.
authors.forename: Sharon
authors.initials: S
authors.lastname: McClellan
authors.affiliation: the Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan 48201.
authors.forename: Linda D
authors.initials: LD
authors.lastname: Hazlett
authors.affiliation: From the Departments of Medicine, Pathology, Case Western Reserve University, Cleveland, Ohio 44106, ghm4@case.edu.
authors.forename: Ganapati H
authors.initials: GH
authors.lastname: Mahabeleshwar
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C490010:Bcl6 protein, mouse; D018925:Chemokines; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; C513258:Prdm1 protein, mouse; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: Kruppel-like factor (KLF); host defense; inflammation; macrophage; vascular biology