German cockroach frass proteases modulate the innate immune response via activation of protease-activated receptor-2.
Allergen exposure can induce an early innate immune response; however, the mechanism by which this occurs has not been addressed. In this report, we demonstrate a role for the active serine proteases in German cockroach (GC) feces (frass) and protease-activated receptor (PAR)-2 in modulating the innate immune response. A single exposure of GC frass induced inflammatory cytokine production and cellular infiltration in the airways of mice. In comparison, exposure to protease-depleted GC frass resulted in diminution of inflammatory cytokine production and airway neutrophilia, but had no effect on macrophage infiltration. Selective activation of PAR-2 confirmed that PAR-2 was sufficient to induce airway inflammation. Exposure of GC frass to PAR-2-deficient mice led to decreased immune responses to GC frass compared to wild-type mice. Using the macrophage as an early marker of the innate immune response, we found that GC frass induced significant release of tumor necrosis factor-alpha from primary alveolar macrophages. This effect was dependent on the intrinsic proteases in GC frass. We confirmed GC frass-induced cytokine expression was mediated by activation of NF-kappaB and ERK in a macrophage cell line. Collectively, these data suggest a central role for GC frass protease-PAR-2 activation in regulating the innate immune response through the activation of alveolar macrophages. Understanding the potential role of protease-PAR-2 activation as a danger signal or adjuvant could yield attractive therapeutic targets.
Day
Scottie B
SB
Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Zhou
Ping
P
Ledford
John R
JR
Page
Kristen
K
D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D003058:Cockroaches / Q000201:enzymology* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005243:Feces / Q000201:enzymology*; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects*; D019476:Insect Proteins / Q000276:immunology / Q000494:pharmacology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D057057:Serine Proteases / Q000276:immunology / Q000494:pharmacology*
D000485:Allergens; D016207:Cytokines; D019476:Insect Proteins; D044464:Receptor, PAR-2; D057057:Serine Proteases