The triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia

PLoS Pathog. 2014 Jun 12;10(6):e1004167. doi: 10.1371/journal.ppat.1004167. eCollection 2014 Jun.

Abstract

Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2(-/-) AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2(-/-) mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Transformed
  • Cells, Cultured
  • Complement C1q / genetics
  • Complement C1q / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal*
  • Female
  • Lung / cytology
  • Lung / immunology*
  • Lung / metabolism
  • Lung / pathology
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / metabolism
  • Macrophages, Alveolar / pathology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration
  • PPAR gamma / metabolism
  • Phagocytosis
  • Pneumonia, Pneumococcal / immunology*
  • Pneumonia, Pneumococcal / metabolism
  • Pneumonia, Pneumococcal / pathology
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / immunology*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Survival Analysis

Substances

  • Cytokines
  • Membrane Glycoproteins
  • PPAR gamma
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • Complement C1q

Associated data

  • GEO/GSE51378