German Cockroach Frass Proteases Cleave Pro-Matrix Metalloproteinase-9

Hughes, Valerie S.; Page, Kristen

doi:10.1080/01902140701356561

Cited by 17 publications

(20 citation statements)

References 38 publications

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“…It has been shown that after disturbance, dust particles containing cockroach proteins Ͼ10 m in diameter may be deposited in the airway (5). GC frass is a complex mixture of a variety of biologically active molecules, including the allergens Bla g 1 and Bla g 2 (27) and active serine proteases and endotoxin (28). Interestingly, our data do not show a role for endotoxin or TLR4 in either neutrophil recruitment or activation.…”

Section: Discussionmentioning

confidence: 37%

TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass

Page

Lierl

Hughes

et al. 2008

The Journal of Immunology

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It is becoming increasingly clear that innate immune mediators play a role in regulating adaptive immune responses in asthma pathogenesis. Cockroach exposure is a major risk factor for the development of asthma. In this study we asked whether German cockroach (GC) feces (frass) could initiate an innate immune response. Naive BALB/c mice were challenged with a single intratracheal inhalation of GC frass. Proinflammatory cytokines were significantly increased in the bronchoalveolar lavage fluid at 3 h and were maintained at higher than baseline levels for at least 24 h. Neutrophil migration into the airways was evident as early as 3 h but was maximal between 6 and 24 h postinhalation. The early increase in cytokine expression was independent of TLR2 or TLR4. Newly infiltrated airway neutrophils were responsible for maintaining high levels of cytokines in the airways. Using neutrophils as an early marker of the innate immune response, we show that show that neutrophils isolated from the airways following GC frass inhalation express TLR2 and release cytokines. GC frass directly affected neutrophil cytokine production via TLR2, but not TLR4, as evidenced by the use of TLR-neutralizing Abs and neutrophils from TLR-deficient mice. Activation of cytokine expression occurred via GC frass-induced NF-κB translocation and DNA binding. These data show that GC frass contains a TLR2 agonist and, to our knowledge, this is the first report of an allergen directly activating cells of the innate immune system via TLR2 and suggests an important link between innate and adaptive immunity.

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Section: Discussionmentioning

confidence: 37%

TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass

Page

Lierl

Hughes

et al. 2008

The Journal of Immunology

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“…To test the role of the proteases and PAR-2 activation on CCL20 release into the airways, we compared BAL levels of CCL20 18 h after a single exposure to GC frass or protease-depleted GC frass. We have previously reported that aprotinin treatment inhibits 85% of the protease activity in GC frass [21] . Exposure to GC frass induced a significant increase in airway CCL20 levels, an effect that was significantly reduced when exposure to protease-depleted GC frass occurred ( fig.…”

Section: Gc Frass Proteases Regulate the Release Of Ccl20 And Gm-csf mentioning

confidence: 99%

“…Protease activity was determined using the Azocoll assay as previously described [19,20] . GC frass was determined to contain 12.3 U/mg and aprotinin treatment inhibited 85% of the protease activity [21] , and will hence be referred to as protease-depleted GC frass. Endotoxin levels were measured using the Limulus Amebocyte Lysate Assay (Lonza, Walkersville, Md., USA).…”

Section: Cockroach Frassmentioning

confidence: 99%

German Cockroach Proteases and Protease-Activated Receptor-2 Regulate Chemokine Production and Dendritic Cell Recruitment

Day¹,

Ledford²,

Zhou³

et al. 2011

J Innate Immun

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We recently showed that serine proteases in German cockroach (GC) feces (frass) decreased experimental asthma through the activation of protease-activated receptor (PAR)-2. Since dendritic cells (DCs) play an important role in the initiation of asthma, we queried the role of GC frass proteases in modulating CCL20 (chemokine C-C motif ligand 20) and granulocyte macrophage colony-stimulating factor (GM-CSF) production, factors that regulate pulmonary DCs. A single exposure to GC frass resulted in a rapid, but transient, increase in GM-CSF and a steady increase in CCL20 in the airways of mice. Instillation of protease-depleted GC frass or instillation of GC frass in PAR-2-deficient mice significantly decreased chemokine release. A specific PAR-2-activating peptide was also sufficient to induce CCL20 production. To directly assess the role of the GC frass protease in chemokine release, we enriched the protease from GC frass and confirmed that the protease was sufficient to induce both GM-CSF and CCL20 production in vivo. Primary airway epithelial cells produced both GM-CSF and CCL20 in a protease- and PAR-2-dependent manner. Finally, we show a decreased percentage of myeloid DCs in the lung following allergen exposure in PAR-2-deficient mice compared to wild-type mice. However, there was no difference in GC frass uptake. Our data indicate that, through the activation of PAR-2, allergen-derived proteases are sufficient to induce CCL20 and GM-CSF production in the airways. This leads to increased recruitment and/or differentiation of myeloid DC populations in the lungs and likely plays an important role in the initiation of allergic airway responses.

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“…Protease activity was determined using the Azocoll assay as previously described [7] . GC frass was determined to contain 19 g protease activity/mg frass and aprotinin treatment inhibited 85% of the protease activity [23] and will hence be referred to as protease-depleted GC frass.…”

Section: Cockroach Frassmentioning

confidence: 99%

German Cockroach Frass Proteases Modulate the Innate Immune Response via Activation of Protease-Activated Receptor-2

et al. 2010

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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-α 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-ĸB 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.

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German Cockroach Frass Proteases Cleave Pro-Matrix Metalloproteinase-9

Cited by 17 publications

References 38 publications

TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass

TLR2-Mediated Activation of Neutrophils in Response to German Cockroach Frass

German Cockroach Proteases and Protease-Activated Receptor-2 Regulate Chemokine Production and Dendritic Cell Recruitment

German Cockroach Frass Proteases Modulate the Innate Immune Response via Activation of Protease-Activated Receptor-2

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