title: KLF6 contributes to myeloid cell plasticity in the pathogenesis of intestinal inflammation.
abstract: Inflammatory bowel disease (IBD) is associated with dysregulated macrophage responses, such that quiescent macrophages acquire a pro-inflammatory activation state and contribute to chronic intestinal inflammation. The transcriptional events governing macrophage activation and gene expression in the context of chronic inflammation such as IBD remain incompletely understood. Here, we identify Kruppel-like transcription factor-6 (KLF6) as a critical regulator of pathogenic myeloid cell activation in human and experimental IBD. We found that KLF6 was significantly upregulated in myeloid cells and intestinal tissue from IBD patients and experimental models of IBD, particularly in actively inflamed regions of the colon. Using complementary gain- and loss-of-function studies, we observed that KLF6 promotes pro-inflammatory gene expression through enhancement of nuclear factor κB (NFκB) signaling, while simultaneously suppressing anti-inflammatory gene expression through repression of signal transducer and activator of transcription 3 (STAT3) signaling. To study the in vivo role of myeloid KLF6, we treated myeloid-specific KLF6-knockout mice (Mac-KLF6-KO) with dextran sulfate sodium (DSS) and found that Mac-KLF6-KO mice were protected against chemically-induced colitis; this highlights the central role of myeloid KLF6 in promoting intestinal inflammation. Collectively, our results point to a novel gene regulatory program underlying pathogenic, pro-inflammatory macrophage activation in the setting of chronic intestinal inflammation.
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Goodman
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Omenetti
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: D
authors.initials: D
authors.lastname: Date
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: L
authors.initials: L
authors.lastname: Di Martino
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: C
authors.initials: C
authors.lastname: De Salvo
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: G-D
authors.initials: GD
authors.lastname: Kim
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Medicine, Division of Gastroenterology, University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chowdhry
authors.affiliation: Academic Department of Gastroenterology, Ethnikon and Kapodistriakon University of Athens and Laikon Hospital, Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Bamias
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Medicine, Division of Gastroenterology, University Hospitals of Cleveland, Cleveland, Ohio, USA.
authors.forename: F
authors.initials: F
authors.lastname: Cominelli
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.|Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: G H
authors.initials: GH
authors.lastname: Mahabeleshwar
mesh_terms: D000818:Animals; D002460:Cell Line; D000066670:Cell Plasticity / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate; D005786:Gene Expression Regulation; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016264:Dextran Sulfate
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