Macrophage inflammatory protein 1alpha/CCL3 is required for clearance of an acute Klebsiella pneumoniae pulmonary infection.
The objective of these studies was to determine the role of macrophage inflammatory protein 1alpha/CCL3 in pulmonary host defense during Klebsiella pneumoniae infection. Following intratracheal inoculation, 7-day survival of CCL3(-/-) mice was less than 10%, compared to 60% for CCL3(+/+) mice. Survival of CCR5(-/-) mice was equivalent to that of controls, indicating that the enhanced susceptibility of CCL3(-/-) mice to K. pneumoniae is mediated via another CCL3 receptor, presumably CCR1. At day 3, CFU burden in the lungs of CCL3(-/-) mice was 800-fold higher than in CCL3(+/+) mice, demonstrating that CCL3 is critical for control of bacterial growth in the lung. Surprisingly, CCL3(-/-) mice had no differences in the recruitment of monocytes/macrophages and even showed enhanced neutrophil recruitment at days 1, 2, and 3 postinfection, compared to CCL3(+/+) mice. Therefore, the defect in clearance was not due to insufficient recruitment of leukocytes. No significant differences in cytokine levels of monocyte chemoattractant protein 1 (MCP-1), interleukin 12, gamma interferon, or tumor necrosis factor alpha in lung lavages were found between CCL3(+/+) and CCL3(-/-) mice. CCL3(-/-) alveolar macrophages were found to have significantly lower phagocytic activity toward K. pneumoniae than CCL3(+/+) alveolar macrophages. These findings demonstrate that CCL3 production is critical for activation of alveolar macrophages to control the pulmonary growth of the gram-negative bacterium K. pneumoniae.
Lindell
D M
DM
Pulmonary and Critical Care Medicine, The University of Michigan Medical School, Ann Arbor, Michigan, USA.
Standiford
T J
TJ
Mancuso
P
P
Leshen
Z J
ZJ
Huffnagle
G B
GB
D000208:Acute Disease; D000818:Animals; D018932:Chemokine CCL2 / Q000032:analysis; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D007711:Klebsiella pneumoniae / Q000276:immunology*; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000166:cytology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D010587:Phagocytosis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma