Inflammatory monocytes orchestrate innate antifungal immunity in the lung

PLoS Pathog. 2014 Feb 20;10(2):e1003940. doi: 10.1371/journal.ppat.1003940. eCollection 2014 Feb.

Abstract

Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2⁺Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2⁺Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2⁺Mo and Mo-DCs exert innate antifungal activity. First, CCR2⁺Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2⁺Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2⁺Mo and their derivatives in innate antifungal immunity in the lung.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillus fumigatus / immunology
  • Cell Differentiation / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Immunity, Innate / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / cytology
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Pulmonary Aspergillosis / immunology*
  • Real-Time Polymerase Chain Reaction
  • Receptors, CCR2 / metabolism
  • Spores, Fungal / immunology

Substances

  • Ccr2 protein, mouse
  • Receptors, CCR2