Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

Zhang, Huiyun; Zeng, Xianlu; He, Shaoheng

doi:10.1155/2014/829068

Cited by 25 publications

(23 citation statements)

References 167 publications

(196 reference statements)

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“…Activation of PAR‐2 leads to production of a variety of inflammatory mediators that are involved in the pathogenesis of asthma . This notion is supported by studies that show association of PAR‐2 with airway inflammation in both people with asthma and animal models of asthma . PAR‐2 is expressed on a variety of cells in the lung including airway epithelium .…”

Section: Introductionmentioning

confidence: 81%

“…Asthma is a common inflammatory airways disease affecting people of all nations with high prevalence in western countries. Different allergens originating from cockroach, house dust mite and ragweed, as well as other sources, play an important role in the pathogenesis of asthma . In response to these allergens, inflammatory and structural cells in the airways produce a variety of mediators such as cytokines, histamine, matrix metalloproteinases, leukotrienes and reactive oxygen species (ROS), which are associated with airway inflammation/remodelling and mucus hypersecretion .…”

Section: Introductionmentioning

confidence: 99%

“…Different allergens originating from cockroach, house dust mite and ragweed, as well as other sources, play an important role in the pathogenesis of asthma . In response to these allergens, inflammatory and structural cells in the airways produce a variety of mediators such as cytokines, histamine, matrix metalloproteinases, leukotrienes and reactive oxygen species (ROS), which are associated with airway inflammation/remodelling and mucus hypersecretion . Reactive oxygen species such as hydrogen peroxide may be directly or indirectly involved in epithelial cell apoptosis, increased vascular permeability and inactivation of antioxidant enzymes, so contributing to asthma symptomatology …”

Section: Introductionmentioning

confidence: 99%

“…Airway epithelial cells (AECs) are constantly exposed to airborne allergens and responsible for key immune responses through a wide range of pattern recognition receptors that respond to danger signals emanating from pathogenic microbes or injured cells . Airborne allergens originating from common household pests such as cockroaches also activate AECs through proteinase‐activated receptor‐2 (PAR‐2).…”

Section: Introductionmentioning

confidence: 99%

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Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

et al. 2015

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SummaryAirway epithelial cells (AECs) express a variety of receptors, which sense danger signals from various aeroallergens/pathogens being inhaled constantly. Proteinase-activated receptor 2 (PAR-2) is one such receptor and is activated by cockroach allergens, which have intrinsic serine proteinase activity. Recently, dual oxidases (DUOX), especially DUOX-2, have been shown to be involved in airway inflammation in response to Toll-like receptor activation. However, the association between PAR-2 and DUOX-2 has not been explored in airways of allergic mice. Therefore, this study investigated the contribution of DUOX-2/reactive oxygen species (ROS) signalling in airway reactivity and inflammation after PAR-2 activation. Mice were sensitized intraperitoneally with intact cockroach allergen extract (CE) in the presence of aluminium hydroxide followed by intranasal challenge with CE. Mice were then assessed for airway reactivity, inflammation, oxidative stress (DUOX-2, ROS, inducible nitric oxide synthase, nitrite, nitrotyrosine and protein carbonyls) and apoptosis (Bax, Bcl-2, caspase-3). Challenge with CE led to up-regulation of DUOX-2 and ROS in AECs with concomitant increases in airway reactivity/inflammation and parameters of oxidative stress, and apoptosis. All of these changes were significantly inhibited by intranasal administration of ENMD-1068, a small molecule antagonist of PAR-2 in allergic mice. Administration of diphenyliodonium to allergic mice also led to improvement of allergic airway responses via inhibition of the DUOX-2/ROS pathway; however, these effects were less pronounced than PAR-2 antagonism. The current study suggests that PAR-2 activation leads to up-regulation of the DUOX-2/ROS pathway in AECs, which is involved in regulation of airway reactivity and inflammation via oxidative stress and apoptosis.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

et al. 2015

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“…Interestingly, PARs are specific targets to initiate protease mediated inflammation [1–3, 82] . Zieske and Bukusoglu [83] demonstrated that protease inhibitors inhibit corneal epithelial migration.…”

Section: Role Of Plasminogen Activator System In Corneal Biologymentioning

confidence: 99%

Role of Protease-Activated Receptors 2 (PAR2) in Ocular Infections and Inflammation

Tripathi

Alizadeh

2014

Receptor Clin Invest

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Protease-activated receptors (PARs) belong to a unique family of G protein-coupled receptors (GPCRs) that are cleaved at an activation site within the N-terminal exodomain by a variety of proteinases, essentially of the serine (Ser) proteinase family. After cleavage, the new N-terminal sequence functions as a tethered ligand, which binds intramolecularly to activate the receptor and initiate signaling. Cell signals induced through the activation of PARs appear to play a significant role in innate and adoptive immune responses of the cornea, which is constantly exposed to proteinases under physiological or pathophysiological conditions. Activation of PARs interferes with all aspects of the corneal physiology such as barrier function, transports, innate and adoptive immune responses, and functions of corneal nerves. It is not known whether the proteinase released from the microorganism can activate PARs and triggers the inflammatory responses. The role of PAR2 expressed by the corneal epithelial cells and activation by serine protease released from microorganism is discussed here. Recent evidences suggest that activation of PAR2, by the serine proteinases, play an important role in innate and inflammatory responses of the corneal infection.

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Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

2015

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Proteases are implicated in exacerbation of allergic diseases. In this study, the role of proteolytic activity of Per a 10 was evaluated on Th2 polarization. Intranasal administration of Per a 10 in mice led to allergic airway inflammation as seen by higher IgE levels, cellular infiltration, IL-17A, and Th2 cytokines, whereas, inactive ( )Per a 10 showed attenuated response. There was an increased OX40L expression on lung and lymph node dendritic cells in Per a 10 immunized group and on Per a 10 stimulated BMDCs. Reduction in CD40 expression without any change at transcript level in lungs of Per a 10 immunized mice suggested CD40 cleavage. BMDCs pulsed with Per a 10 showed reduced CD40 expression with lower IL-12p70 secretion as compared to heat inactivated Per a 10. IL-23, TNF-α, and IL-6 levels were significantly higher in Per a 10 stimulated BMDCs supernatant. In DC-T cell coculture studies, Per a 10 pulsed BMDCs showed higher levels of IL-4 and IL-13 that were reduced on blocking of either IL-23 or OX40L. In conclusion, the data suggests a critical role of protease activity of Per a 10 in promoting Th2 polarization by increasing IL-23 secretion and OX40L expression on dendritic cells.Keywords: CD40 r Cytokines r Dendritic cell r OX40L r Protease allergen Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionProteases are known to play an important role in manifestation of diseases like cancer, coagulopathies, respiratory inflammatory diseases, rheumatoid arthritis, and degenerative diseases [1][2][3]. Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7]. Further, cleavage and subsequent activation of PAR receptors by proteases lead to increased secretion of chemokines, proinflammatory, and pro Th2 cytokines from airway epithelial cells [8,9]. Studies have reported impaired epithelial barrier function as the feature of allergic diseases like asthma and atopic dermatitis [10]. The enzymatic activity of proteases has been reported to compromise epithelial barrier directly by cleaving tight junction proteins ZO-1 and occludin thereby increasing epithelial permeability [11,12]. Proteases can also act as adjuvants to bystander allergens present in the same microenvironment [13,14].Cockroaches have emerged as an important source of indoor allergens worldwide and cockroach extract is shown to be rich in proteases [15]. Previously, Per a 10, a serine protea...

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Evaluation on Potential Contributions of Protease Activated Receptors Related Mediators in Allergic Inflammation

Cited by 25 publications

References 167 publications

Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

Proteinase activated receptor‐2‐mediated dual oxidase‐2 up‐regulation is involved in enhanced airway reactivity and inflammation in a mouse model of allergic asthma

Role of Protease-Activated Receptors 2 (PAR2) in Ocular Infections and Inflammation

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

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