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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
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CC chemokine receptor 4 modulates Toll-like receptor 9-mediated innate immunity and signaling

Makoto Ishii1, Cory M Hogaboam, Amrita Joshi

  • 1Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.

European Journal of Immunology
|July 16, 2008
PubMed

Insights

CC chemokine receptor 4 (CCR4) deficiency protects against sepsis by altering Toll-like receptor 9 (TLR9) signaling in macrophages. CCR4-deficient macrophages show impaired TLR9 responses, suggesting a regulatory role in innate immunity.

Area of Science:

  • Immunology
  • Innate Immunity
  • Molecular Mechanisms

Background:

  • Toll-like receptor 9 (TLR9) plays a crucial role in innate immune responses to microbial DNA.
  • CC chemokine receptor 4 (CCR4) is implicated in immune cell trafficking and modulation.
  • Understanding the interplay between CCR4 and TLR9 is essential for developing novel immunotherapies.

Purpose of the Study:

  • To investigate the modulatory role of CCR4 in TLR9-mediated innate immunity.
  • To elucidate the molecular mechanisms underlying CCR4's influence on TLR9 signaling.
  • To assess the therapeutic potential of targeting CCR4 in sepsis models.

Main Methods:

  • Utilized CCR4-deficient mice and wild-type (WT) littermates.
  • Induced experimental models of sepsis: cecal ligation and puncture (CLP) and CpG DNA/D-galactosamine shock.
  • Analyzed Toll-like receptor 9 (TLR9) signaling pathways (MAPK/AP-1, PI3K/Akt, IKK/NF-kappaB) in bone marrow-derived macrophages (BMMPhi).
  • Assessed CpG DNA internalization and cytokine expression.
  • Investigated macrophage phenotypes (M1 vs. M2).

Main Results:

  • CCR4-deficient mice exhibited resistance to sepsis induction.
  • TLR9-mediated signaling pathways (MAPK/AP-1, PI3K/Akt, IKK/NF-kappaB) were impaired in CCR4-deficient macrophages.
  • Internalization of CpG DNA was increased in CCR4-deficient macrophages.
  • CCR4-deficient macrophages displayed an alternatively activated (M2) phenotype.
  • Impaired TLR9 signaling in CCR4-deficient cells mirrored responses in M2-polarized WT macrophages.

Conclusions:

  • Macrophages deficient in CCR4 exert a regulatory influence on TLR9-mediated innate immunity.
  • CCR4 plays a significant role in modulating TLR9-driven inflammatory responses.
  • Targeting CCR4 may offer a therapeutic strategy for sepsis and other TLR9-related inflammatory conditions.

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