CC chemokine receptor 4 modulates Toll-like receptor 9-mediated innate immunity and signaling

Makoto Ishii, Cory M. Hogaboam, Amrita Joshi, Toshihiro Ito, Daniel J. Fong, Steven L. Kunkel

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


The present study addressed the modulatory role of CC chemokine receptor 4 (CCR4) in Toll-like receptor (TLR) 9-mediated innate immunity and explored the underlying molecular mechanisms. Our results demonstrated that CCR4-deficient mice were resistant to both septic peritonitis induced by cecal ligation and puncture (CLP) and CpG DNA/ D-galactosamine-induced shock. In bone marrow-derived macrophages (BMMΦ) from CLP-treated CCR4-deficient mice, TLR9-mediated pathways of MAPK/AP-1, PI3K/Akt, and IκB kinase (IKK)/NF-κB were impaired compared to wild-type (WT) cells. While TLR9 expression was not altered, the intensity of internalized CpG DNA was increased in CCR4-deficient macrophages when compared to WT macrophages. Pharmacological inhibitor studies revealed that impaired activation of JNK, PI3K/Akt, and/or IKK/NF-κB could be responsible for decreased proinflammatory cytokine expression in CCR4-deficient macrophages. Interestingly, the CCR4-deficient BMMΦ exhibited an alternatively activated (M2) phenotype and the impaired TLR9-mediated signal transduction responses in CCR4-deficient cells were similar to the signaling responses observed in WT BMMΦ skewed to an alternatively activated phenotype. These results indicate that macrophages deficient in CCR4 impart a regulatory influence on TLR9-mediated innate immunity.

Original languageEnglish
Pages (from-to)2290-2302
Number of pages13
JournalEuropean Journal of Immunology
Issue number8
Publication statusPublished - 2008 Aug
Externally publishedYes


  • Chemokines
  • Macrophages
  • Tool-like receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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