Role of PAR2 in murine pulmonary pseudomonal infection.
Proteinases can influence lung inflammation by various mechanisms, including via cleavage and activation of protease-activated receptors (PAR) such as PAR2. In addition, proteinases such as neutrophil and/or Pseudomonas-derived elastase can disarm PAR2 resulting in loss of PAR2 signaling. Currently, the role of PAR2 in host defense against bacterial infection is not known. Using a murine model of acute Pseudomonas aeruginosa pneumonia, we examined differences in the pulmonary inflammatory response between wild-type and PAR2(-/-) mice. Compared with wild-type mice, PAR2(-/-) mice displayed more severe lung inflammation and injury in response to P. aeruginosa infection as indicated by higher bronchoalveolar lavage fluid neutrophil numbers, protein concentration, and TNF-alpha levels. By contrast, IFN-gamma levels were markedly reduced in PAR2(-/-) compared with wild-type mice. Importantly, clearance of P. aeruginosa was diminished in PAR2(-/-) mice. In vitro testing revealed that PAR2(-/-) neutrophils killed significantly less bacteria than wild-type murine neutrophils. Further, both neutrophils and macrophages from PAR2(-/-) mice displayed significantly reduced phagocytic efficiency compared with wild-type phagocytes. Stimulation of PAR2 on macrophages using a PAR2-activating peptide resulted in enhanced phagocytosis directly implicating PAR2 signaling in the phagocytic process. We conclude that genetic deletion of PAR2 is associated with decreased clearance of P. aeruginosa. Our data suggest that a deficiency in IFN-gamma production and impaired bacterial phagocytosis are two potential mechanisms responsible for this defect.
Moraes
Theo J
TJ
Academic Affairs, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA.
Martin
Raiza
R
Plumb
Jonathan D
JD
Vachon
Eric
E
Cameron
Cheryl M
CM
Danesh
Ali
A
Kelvin
David J
DJ
Ruf
Wolfram
W
Downey
Gregory P
GP
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D018375:Neutrophil Activation; D009504:Neutrophils / Q000166:cytology / Q000382:microbiology; D010587:Phagocytosis; D011014:Pneumonia / Q000382:microbiology; D011552:Pseudomonas Infections / Q000378:metabolism* / Q000382:microbiology; D011550:Pseudomonas aeruginosa; D044464:Receptor, PAR-2 / Q000172:deficiency / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000378:metabolism* / Q000382:microbiology*; D015398:Signal Transduction
D016207:Cytokines; D044464:Receptor, PAR-2