CC chemokine receptor 4 modulates Toll-like receptor 9-mediated innate immunity and signaling.
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 (BMMPhi) from CLP-treated CCR4-deficient mice, TLR9-mediated pathways of MAPK/AP-1, PI3K/Akt, and IkappaB kinase (IKK)/NF-kappaB 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-kappaB could be responsible for decreased proinflammatory cytokine expression in CCR4-deficient macrophages. Interestingly, the CCR4-deficient BMMPhi 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 BMMPhi skewed to an alternatively activated phenotype. These results indicate that macrophages deficient in CCR4 impart a regulatory influence on TLR9-mediated innate immunity.
Ishii
Makoto
M
Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Hogaboam
Cory M
CM
Joshi
Amrita
A
Ito
Toshihiro
T
Fong
Daniel J
DJ
Kunkel
Steven L
SL
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D054398:Receptors, CCR4 / Q000502:physiology*; D018805:Sepsis / Q000276:immunology; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C515355:Ccr4 protein, mouse; C520220:CpG-N ODN208; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D054398:Receptors, CCR4; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases