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Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation. Am J Physiol Gastrointest Liver Physiol 2015 Dec 01;309(11):G900-9

Date

10/17/2015

Pubmed ID

26472224

Pubmed Central ID

PMC4669350

DOI

10.1152/ajpgi.00309.2015

Scopus ID

2-s2.0-84949188711 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Papadakis KA, Krempski J, Svingen P, Xiong Y, Sarmento OF, Lomberk GA, Urrutia RA, Faubion WA

Author

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Acetylation
Animals
Base Sequence
Binding Sites
CD11b Antigen
CX3C Chemokine Receptor 1
Colitis
Colon
Dextran Sulfate
Disease Models, Animal
Early Growth Response Transcription Factors
Genetic Predisposition to Disease
Histocompatibility Antigens Class II
Histones
Inflammation Mediators
Interleukin-10
Intestinal Mucosa
Kruppel-Like Transcription Factors
Macrophages
Mice, Knockout
Molecular Sequence Data
Phenotype
Phosphorylation
Promoter Regions, Genetic
Receptors, Chemokine
Receptors, Transforming Growth Factor beta
Signal Transduction
Smad2 Protein
Tumor Necrosis Factor-alpha