The CCL7-CCL2-CCR2 axis regulates IL-4 production in lungs and fungal immunity

Wendy A. Szymczak, George S. Deepe

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Expression of the chemokine receptor CCR2 can be detrimental or beneficial for infection resolution. Herein, we examined whether CCR2 was requisite for control of infection by the dimorphic fungus Histoplasma capsulatum. H. capsulatum-infected CCR2-/- mice manifested defects in inflammatory cell recruitment, increased IL-4, and progressive infection. Increased IL-4 in CCR2-/- mice primarily contributed to decreased host resistance as demonstrated by the ability of IL-4-neutralized CCR2-/- mice to resolve infection without altering inflammatory cell recruitment. Surprisingly, numerous alveolar macrophages and dendritic cells contributed to IL-4 production in CCR2-/- mice. IL-4-mediated impairment of immunity in CCR2 -/- mice was associated with increased arginase-1 and YM1 transcription and increased transferrin receptor expression by phagocytic cells. Immunity in mice lacking the CCR2 ligand CCL2 was not impaired despite decreased inflammatory cell recruitment. Neutralization of the CCR2 ligand CCL7 in CCL2-/- mice, but not wild type, resulted in increased IL-4 and fungal burden. Thus, CCL7 in combination with CCL2 limits IL-4 generation and exerts control of host resistance. Furthermore, increased phagocyte-derived IL-4 in CCR2-/- mice is associated with the presence of alternatively activated phagocytic cells.

Original languageEnglish (US)
Pages (from-to)1964-1974
Number of pages11
JournalJournal of Immunology
Volume183
Issue number3
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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