Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation

Konstantinos A. Papadakis, James Krempski, Phyllis Svingen, Yuning Xiong, Olga F. Sarmento, Gwen A. Lomberk, Raul A. Urrutia, William A. Faubion

Research output: Contribution to journalArticle

10 Scopus 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+CX3CR1hi 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.

Original languageEnglish (US)
Pages (from-to)G900-G909
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number11
DOIs
StatePublished - 2015

Keywords

  • Colitis
  • Colonic macrophages
  • Epigenetics
  • Histone acetyl transferase
  • Krüppel-like factor

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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