Age-related defects in TLR2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia

Angela R. Boyd, Pooja Shivshankar, Shoulei Jiang, Michael T. Berton, Carlos J. Orihuela

Research output: Contribution to journalArticle

60 Scopus citations

Abstract

Alveolar macrophages (AMs) are the first immune cells to respond to an invading pathogen and coordinate the inflammatory response within the lungs. Studies suggest that macrophages exhibit age-related deficiencies in Toll-like receptor (TLR) function; however, the impact of this dysfunction during pneumonia, the leading cause of infectious death in the elderly, and the underlying mechanisms responsible remain unclear. We examined disease severity in young, mature, and aged BALB/cBy mice following intratracheal infection with the Gram-positive bacteria . Streptococcus pneumoniae (Spn). Both mature and aged mice failed to clear bacteria and as a result had increased mortality, tissue damage and vascular leakage. Early production of TNFα, IL-1β, and IL-6 during pneumonia declined with age and was associated with an inability of isolated AMs to respond to pneumococcal cell wall (CW) and ethanol-killed Spn ex vivo. . Total levels of TLR1 were unaffected by age and TLR2 surface expression was slightly yet significantly increased on aged AMs suggesting that intracellular TLR signaling defects were responsible for the age-related decline in cytokine responsiveness. Following infection of isolated AMs with live Spn, a significant age-related decline in TLR2-induced phosphorylation of p65 NFκB, JNK and p38 MAPK, and an increase in ERK phosphorylation was observed by immunoblotting. These data are the first to demonstrate that TLR2-dependent recognition of Spn by aged AMs is impaired and is associated with a delayed pro-inflammatory cytokine response in vivo along with enhanced susceptibility to pneumococcal pneumonia.

Original languageEnglish (US)
Pages (from-to)507-518
Number of pages12
JournalExperimental Gerontology
Volume47
Issue number7
DOIs
StatePublished - Jul 1 2012

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Keywords

  • Aging
  • Interleukin-6
  • MAPK
  • Macrophages
  • NFκB
  • Pneumonia
  • Streptococcus pneumoniae
  • Toll-like receptor
  • Tumor necrosis factor α

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Cell Biology

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