title: Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation.
abstract: Krüppel-like factor (KLF)-10 is an important transcriptional regulator of TGF-β1 signaling in both CD8(+) and CD4(+) T lymphocytes. In the present study, we demonstrate a novel role for KLF10 in the regulation of TGFβRII expression with functional relevance in macrophage differentiation and activation. We first show that transfer of KLF10(-/-) bone marrow-derived macrophages into wild-type (WT) mice leads to exacerbation of experimental colitis. At the cell biological level, using two phenotypic strategies, we show that KLF10-deficient mice have an altered colonic macrophage phenotype with higher frequency of proinflammatory LyC6(+)MHCII(+) cells and a reciprocal decrease of the anti-inflammatory LyC6(-)MHCII(+) subset. Additionally, the anti-inflammatory CD11b(+)CX3CR1(hi) subset of colonic macrophages is significantly decreased in KLF10(-/-) compared with WT mice under inflammatory conditions. Molecularly, CD11b(+) colonic macrophages from KLF10(-/-) mice exhibit a proinflammatory cytokine profile with increased production of TNF-α and lower production of IL-10 in response to LPS stimulation. Because KLF10 is a transcription factor, we explored how this protein may regulate macrophage function. Consequently, we analyzed the expression of TGFβRII expression in colonic macrophages and found that, in the absence of KLF10, macrophages express lower levels of TGFβRII and display an attenuated Smad-2 phosphorylation following TGF-β1 stimulation. We further show that KLF10 directly binds to the TGFβRII promoter in macrophages, leading to enhanced gene expression through histone H3 acetylation. Collectively, our data reveal a critical role for KLF10 in the epigenetic regulation of TGFβRII expression in macrophages and the acquisition of a "regulatory" phenotype that contributes to intestinal mucosal homeostasis.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and papadakis.konstantinos@mayo.edu.
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: James
authors.initials: J
authors.lastname: Krempski
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Phyllis
authors.initials: P
authors.lastname: Svingen
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: Olga F
authors.initials: OF
authors.lastname: Sarmento
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Departments of Medicine and Biochemistry and Molecular Biology, Epigenetic Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gwen A
authors.initials: GA
authors.lastname: Lomberk
authors.affiliation: Epigenetics and Chromatin Dynamics Laboratory, Departments of Medicine and Biochemistry and Molecular Biology, Epigenetic Translational Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; and.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
mesh_terms: D000107:Acetylation; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D039481:CD11b Antigen / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D051765:Early Growth Response Transcription Factors / Q000172:deficiency* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism* / Q000637:transplantation; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D019707:Receptors, Chemokine / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D051765:Early Growth Response Transcription Factors; D000949:Histocompatibility Antigens Class II; D006657:Histones; C556062:IL10 protein, mouse; D018836:Inflammation Mediators; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D019707:Receptors, Chemokine; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016264:Dextran Sulfate; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Krüppel-like factor; colitis; colonic macrophages; epigenetics; histone acetyl transferase