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CCR4 is a key modulator of innate immune responses

Traci L Ness1, Jillian L Ewing, Cory M Hogaboam

  • 1Department of Pathology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|November 23, 2006
PubMed

Insights

Mice lacking the CCR4 receptor show enhanced resistance to pathogens and endotoxins. This resistance is linked to improved immune cell function and signaling pathways, highlighting CCR4's role in innate immunity.

Area of Science:

  • Immunology
  • Innate Immunity
  • Macrophage Biology

Background:

  • Chemokine receptor CCR4 (C-C chemokine receptor type 4) is primarily known for its role in T-helper 2 (Th2) cell-mediated immune responses.
  • Its function in innate immunity and response to pathogens remains largely unexplored.
  • Previous research indicated CCR4-deficient mice exhibit resistance to lipopolysaccharide (LPS)-induced lethality.

Purpose of the Study:

  • To investigate the role of CCR4 in innate immune responses against various pathogens and Toll-like receptor (TLR) agonists.
  • To elucidate the underlying mechanisms of CCR4-mediated regulation of innate immunity and macrophage function.

Main Methods:

  • Utilized CCR4-deficient (CCR4(-/-)) and wild-type (WT) mice models.
  • Challenged mice with TLR agonists and bacterial peritonitis models.
  • Assessed leukocyte recruitment, TLR expression, cytokine/chemokine profiles, bacterial clearance, macrophage activation markers (e.g., FIZZ1), and intracellular signaling pathways (NF-kappaB, p38 MAPK, JNK).

Main Results:

  • CCR4(-/-) mice demonstrated significant resistance to TLR agonists and bacterial peritonitis compared to WT mice.
  • Resistance was correlated with enhanced early leukocyte recruitment, increased TLR expression, a type 2 skewed cytokine profile, and superior bacterial clearance.
  • CCR4(-/-) macrophages displayed features of alternatively activated macrophages, with down-regulated MyD88-dependent NF-kappaB signaling and increased p38 MAPK and JNK activation.

Conclusions:

  • CCR4 plays a crucial role in regulating innate immune responses and macrophage differentiation.
  • Absence of CCR4 enhances resistance to pathogens by modulating TLR signaling and promoting an alternatively activated macrophage phenotype.
  • These findings underscore the importance of chemokine receptor expression in the regulation of innate immunity and TLR signaling pathways.

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