The role of protease-activated receptor-2 on pulmonary neutrophils in the innate immune response to cockroach allergen

Abstract

BackgroundSerine proteases in German cockroach (GC) have been shown to mediate allergic airway inflammation through the activation of protease activated receptor (PAR)-2. Neutrophils play an important role in regulating the innate immune response, and are recruited into the airways following GC frass exposure. As such, we investigated the role of PAR-2 in airway neutrophil recruitment, activation and cytokine production following allergen exposure.MethodsWild type and PAR-2-deficient mice were administered a single intratracheal instillation of PBS or GC frass and neutrophil recruitment, expression of PAR-2, CD80, CD86, and MHC class II were assessed by flow cytometry and levels of tumor necrosis factor (TNF)α was assessed by ELISA. Uptake of AlexaFluor 405-labeled GC frass by neutrophils was performed by flow cytometry.ResultsNeutrophil recruitment in the lung and airways following GC frass exposure was significantly decreased in PAR-2-deficient mice compared to wild type mice. GC frass exposure increased the level of PAR-2 on pulmonary neutrophils and increased numbers of PAR-2-positive neutrophils were found in the lungs; however PAR-2 did not play a role in meditating allergen uptake. Comparing wild type and PAR-2-deficient mice, we found that a single exposure to GC frass increased levels of CD80 and CD86 on pulmonary neutrophils, an effect which was independent of PAR-2 expression. Neutrophils isolated from the whole lungs of naïve PAR-2-deficient mice treated ex vivo with GC frass produced significantly less TNFα than in similarly treated wild type neutrophils. Lastly, neutrophils were isolated from the bronchoalveolar lavage fluid of wild type and PAR-2-deficient mice following a single intratracheal exposure to GC frass. Airway neutrophils from PAR-2-deficient mice released substantially decreased levels of TNFα, suggesting a role for PAR-2 in neutrophil-derived cytokine production.ConclusionsTogether these data suggest PAR-2 expression can be upregulated on lung neutrophils following allergen exposure and the consequence is altered release of TNFα which could drive the early innate immune response.

Gingival crevicular fluid levels of protease‐activated receptors type 1 and type 2 in diabetic patients with periodontitis

“…Corroborating with this evidence, a previous study from our group showed that salivary HBD‐2 levels and PAR 2 expression from gingival crevicular fluid are higher in subjects with chronic periodontitis than in healthy subjects . In addition, PAR 2 activation has also been associated with neutrophil recruitment , another early innate response that plays an important role in periodontal pathogenesis due to the microbicidal machinery of neutrophils. Thus, it can be suggested that PAR 2 downregulation in diabetics with periodontitis might lead to an impaired response against periodontal pathogens and consequently increase the susceptibility and severity of periodontitis.…”

Stenotrophomonas maltophilia Serine Protease StmPr1 Induces Matrilysis, Anoikis, and Protease-Activated Receptor 2 Activation in Human Lung Epithelial Cells

“…S. maltophilia induces inflammation and neutrophil recruitment in the murine lung, and activation of both PAR1 and PAR2 has been shown to increase neutrophil recruitment to the lung in vivo, which results in increased tissue damage and impairs the host response (62,63). Our data presented here suggest that StmPr1-induced PAR signaling may contribute to S. maltophilia-mediated inflammation in the lung.…”

Aspergillus fumigatus Increased PAR-2 Expression and Elevated Proinflammatory Cytokines Expression Through the Pathway of PAR-2/ERK1/2 in Cornea

“…22 TNF-a expression substantially decreased in airway neutrophils from PAR-2-deficient mice, which suggested a role for PAR-2 in neutrophil-derived cytokine production. 23 To further determine the role of PAR-2 in A. fumigatus keratitis, FSLLRY-NH 2 was used to selectively inhibit PAR-2 and then further confirmed the importance of PAR-2 in A. fumigatus keratitis. Results indicated that FSLLRY-NH 2 treatment significantly decreased mRNA levels of IL-1b, TNF-a, IFN-c, and MIP-2 in comparison with infected control corneas.…”