Protease-Activated Receptor-2 Signaling Triggers Dendritic Cell Development

Fields, Ryan C.; Schoenecker, Jonathan G.; Hart, Justin P.; Hoffman, Maureane; Pizzo, Salvatore V.; Lawson, Jeffrey H.

doi:10.1016/s0002-9440(10)64316-7

Cited by 73 publications

(57 citation statements)

References 32 publications

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“…The use of PAR-2 knockout mice could show lack of mucosal sensitization to HDM in the absence of PAR-2, but there are potential problems with this approach. PAR-2 knockout mice develop significantly lower AHR and airway inflammation compared with normal controls (38), and these mice may have DC developmental defects and, therefore, Ag presentation may be greatly hindered in vivo (39). Thus, one would be unable to discern whether an apparent lack of allergic sensitization is due to the absence of PAR-2 in the airways or defects in Ag presentation.…”

Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway

Ebeling

Lam

Gordon

et al. 2007

The Journal of Immunology

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The reason why particular inhaled Ags induce allergic sensitization while others lead to immune tolerance is unclear. Along with a genetic predisposition to atopy, intrinsic characteristics of these Ags must be important. A common characteristic of many allergens is that they either possess proteinase activity or are inhaled in particles rich in proteinases. Many allergens, such as house dust mite and cockroach allergens, have the potential to activate the proteinase-activated receptor (PAR)-2. In this study, we report that PAR-2 activation in the airways at the same time as exposure to inhaled Ags induces allergic sensitization, whereas exposure to Ag alone induces tolerance. BALB/c mice were administered OVA with a PAR-2 activating peptide intranasally. Upon allergen re-exposure mice developed airway inflammation and airway hyperresponsiveness, as well as OVA-specific T cells with a Th2 cytokine profile when restimulated with OVA in vitro. Conversely, mice given OVA alone or OVA with a PAR-2 control peptide developed tolerance. These tolerant mice did not develop airway inflammation or airway hyperresponsiveness, and developed OVA-specific T cells that secreted high levels of IL-10 when restimulated with OVA in vitro. Furthermore, pulmonary dendritic cell trafficking was altered in mice following intranasal PAR-2 activation. Finally, we showed that PAR-2-mediated allergic sensitization was TNF-dependent. Thus, PAR-2 activation in the airways could be a critical factor in the development of allergic sensitization following mucosal exposure to allergens with serine proteinase activity. Interfering with this pathway may prove to be useful for the prevention or treatment of allergic diseases.

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Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway

Ebeling

Lam

Gordon

et al. 2007

The Journal of Immunology

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show abstract

“…Similarly, PAR-2 has its N-terminal self-binding site unavailable until cleaved by serine proteases; the receptor then facilitates release of IL-1β, IL-6, IL-8 and TNF-α and increases neutrophil motility. Dendritic cells mature on activation of PAR-2; accordingly, bone marrow cells from mice that lack PAR-2 fail to mature under in vitro protocols (33). Protease-activated receptors are also implicated in cardiovascular diseases (34), implying that intervening with their activation by AAT may interfere with relevant pathological pathways.…”

Section: Molecular Targets Of Aat Closely Relate To Inflammationmentioning

confidence: 99%

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Lewis

2012

Mol Med

146

115

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α 1 -Antitrypsin (AAT) is a 52-kDa circulating serine protease inhibitor. Production of AAT by the liver maintains 0.9-1.75 mg/mL circulating levels. During acute-phase responses, circulating AAT levels increase more than fourfold. In individuals with one of several inherited mutations in AAT, low circulating levels increase the risk for lung, liver and pancreatic destructive diseases, particularly emphysema. These individuals are treated with lifelong weekly infusions of human plasma-derived AAT. An increasing amount of evidence appears to suggest that AAT possesses not only the ability to inhibit serine proteases, such as elastase and proteinase-3 (PR-3), but also to exert antiinflammatory and tissue-protective effects independent of protease inhibition. AAT modifies dendritic cell maturation and promotes T regulatory cell differentiation, induces interleukin (IL)-1 receptor antagonist and IL-10 release, protects various cell types from cell death, inhibits caspases-1 and -3 activity and inhibits IL-1 production and activity. Importantly, unlike classic immunosuppressants, AAT allows undeterred isolated T-lymphocyte responses. On the basis of preclinical and clinical studies, AAT therapy for nondeficient individuals may interfere with disease progression in type 1 and type 2 diabetes, acute myocardial infarction, rheumatoid arthritis, inflammatory bowel disease, cystic fibrosis, transplant rejection, graft versus host disease and multiple sclerosis. AAT also appears to be antibacterial and an inhibitor of viral infections, such as influenza and human immunodeficiency virus (HIV), and is currently evaluated in clinical trials for type 1 diabetes, cystic fibrosis and graft versus host disease. Thus, AAT therapy appears to have advanced from replacement therapy, to a safe and potential treatment for a broad spectrum of inflammatory and immune-mediated diseases.

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“…Up-regulation of PAR-2 in inflamed synovial tissues was also demonstrated in the arthritis, suggesting the pro-inflammatory effects of PAR-2 mainly at the local tissues. However, involvement of PAR-2 in immune responses should also be considered, as the effect of PAR-2 on dendritic cell development (24). Other reports using PAR-2-gene-deficient mice demon- strated important roles of PAR-2 in hyperalgesia (25) and intestinal inflammation (26), which may coordinate neurogenic inflammation and pain.…”

Section: Physiological Studies Using Par-2-gene-deficient Micementioning

confidence: 99%

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

et al. 2005

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Abstract. PAR-2 is the second member of the family of proteinase-activated receptors activated by trypsin, tryptase, and several other serine proteinases. In order to evaluate the therapeutic potential for PAR-2, we have performed studies on PAR-2-mediated signal transduction and investigated the effects of PAR-2 gene deficiency in disease models. In addition to the Gprotein-coupled receptor-mediated common signal transduction pathways, inositol 1,4,5-trisphosphate production and mobilization of Ca

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Protease-Activated Receptor-2 Signaling Triggers Dendritic Cell Development

Cited by 73 publications

References 32 publications

Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway

Proteinase-Activated Receptor-2 Promotes Allergic Sensitization to an Inhaled Antigen through a TNF-Mediated Pathway

Expanding the Clinical Indications for α1-Antitrypsin Therapy

Physiology and Pathophysiology of Proteinase-Activated Receptors (PARs): PAR-2 as a Potential Therapeutic Target

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