Alternaria alternata-induced airway epithelial signaling and inflammatory responses via protease-activated receptor-2 expression

Rivas, Candy; Schiff, Hillary; Moutal, Aubin; Khanna, Rajesh; Kiela, Pawel R.; Dussor, Gregory; Price, Theodore J.; Vagner, Josef; DeFea, Kathryn; Boitano, Scott

doi:10.1016/j.bbrc.2021.12.090

Cited by 11 publications

(9 citation statements)

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“…In these experiments, cell index was allowed to stabilize for 90 min prior to antagonist/agonist treatment. Agonist concentrations approximate the EC 80 values (Rivas et al, 2022).…”

Section: Methodsmentioning

confidence: 76%

“…We next evaluated the potential for C781 to antagonize enzymatic activation of PAR2 by monitoring PAR2‐dependent signalling responses of 16HBE14o‐ cells to both trypsin and human neutrophil elastase. Both trypsin and elastase induced concentration‐dependent signalling with 16HBE14o‐ cells and RTCA that were dependent on PAR2 expression (Rivas et al, 2022). As with the PAR2 ligand, C781 effectively reduced 30 nM trypsin‐ and elastase‐induced in vitro physiological signalling in a concentration dependent manner (Figure 1b, c).…”

Section: Resultsmentioning

confidence: 99%

“…RTCA is a high-capacity cell signalling detection platform that uses impedance to monitor physiological response (Atienza et al, 2006;Xi et al, 2008). We have extensively demonstrated the ability to detect PAR2 signalling with this device (Boitano et al, 2014(Boitano et al, , 2015Flynn et al, 2011Flynn et al, , 2013Rivas et al, 2022). Briefly, a background measurement was taken using 50 μl 2% FBS-supplemented MEM per well in an E96 plate (Agilent Technologies, Santa Clara, CA).…”

Section: In Vitro Physiological Response With the Xcelligence Real Ti...mentioning

confidence: 99%

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β‐Arrestin‐biased proteinase‐activated receptor‐2 antagonist C781 limits allergen‐induced airway hyperresponsiveness and inflammation

Schiff

Rivas

Pederson

et al. 2022

British J Pharmacology

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Background and Purpose Asthma is a heterogenous disease strongly associated with inflammation that has many different causes and triggers. Current asthma treatments target symptoms such as bronchoconstriction and airway inflammation. Despite recent advances in biological therapies, there remains a need for new classes of therapeutic agents with novel, upstream targets. The proteinase‐activated receptor‐2 (PAR2) has long been implicated in allergic airway inflammation and asthma and it remains an intriguing target for novel therapies. Here, we describe the actions of C781, a newly developed low MW PAR2 biased antagonist, in vitro and in vivo in the context of acute allergen exposure. Experimental Approach A human bronchial epithelial cell line expressing PAR2 (16HBE14o‐ cells) was used to evaluate the modulation in vitro, by C781, of physiological responses to PAR2 activation and downstream β‐arrestin/MAPK and Gq/Ca2+ signalling. Acute Alternaria alternata sensitized and challenged mice were used to evaluate C781 as a prophylactically administered modulator of airway hyperresponsiveness, inflammation and mucus overproduction in vivo. Key Results C781 reduced in vitro physiological signalling in response to ligand and proteinase activation. C781 effectively antagonized β‐arrestin/MAPK signalling without significant effect on Gq/Ca2+ signalling in vitro. Given prophylactically, C781 modulated airway hyperresponsiveness, airway inflammation and mucus overproduction of the small airways in an acute allergen‐challenged mouse model. Conclusion and Implications Our work demonstrates the first biased PAR2 antagonist for β‐arrestin/MAPK signalling. C781 is efficacious as a prophylactic treatment for allergen‐induced airway hyperresponsiveness and inflammation in mice. It exemplifies a key pharmacophore for PAR2 that can be optimized for clinical development.

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“…In these experiments, cell index was allowed to stabilize for 90 min prior to antagonist/agonist treatment. Agonist concentrations approximate the EC 80 values (Rivas et al, 2022).…”

Section: Methodsmentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: In Vitro Physiological Response With the Xcelligence Real Ti...mentioning

confidence: 99%

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β‐Arrestin‐biased proteinase‐activated receptor‐2 antagonist C781 limits allergen‐induced airway hyperresponsiveness and inflammation

Schiff

Rivas

Pederson

et al. 2022

British J Pharmacology

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“…111,112 Alternaria alkaline serine protease activates PAR2 directly and induces allergic airway inflammation in mice. 106 Additionally, various fungal allergen extracts, including Alternaria 113,114 and Aspergillus 115 extracts, have been shown to activate AEC, eosinophils, and induce cytokines through PAR2 but the exact proteases mediating these effects have not been identified. 116 Fungal Pen c 13 can cleave PAR1 and PAR2 at their activation sites and desensitize AECs to increased intracellular calcium induced by PAR1 and PAR2 agonists.…”

Section: Prote a S E-ac Tivated Recep Tor (Par ) Ac Tivati On By Prot...mentioning

confidence: 99%

Protease allergens as initiators–regulators of allergic inflammation

Soh¹,

Zhang

Hollenberg

et al. 2023

Allergy

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Tremendous progress in the last few years has been made to explain how seemingly harmless environmental proteins from different origins can induce potent Th2-biased inflammatory responses. Convergent findings have shown the key roles of allergens displaying proteolytic activity in the initiation and progression of the allergic response. Through their propensity to activate IgE-independent inflammatory pathways, certain allergenic proteases are now considered as initiators for sensitization to themselves and to non-protease allergens. The protease allergens degrade junctional proteins of keratinocytes or airway epithelium to facilitate allergen delivery across the epithelial barrier and their subsequent uptake by antigen-presenting cells. Epithelial injuries mediated by these proteases together with their sensing by protease-activated receptors (PARs) elicit potent inflammatory responses resulting in the release of pro-Th2 cytokines (IL-6, IL-25, IL-1β, TSLP) and danger-associated molecular patterns (DAMPs; IL-33, ATP, uric acid). Recently, protease allergens were shown to cleave the protease sensor domain of IL-33 to produce a super-active form of the alarmin. At the same | 1149 SOH et al.

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“…Pen ch 13 also directly degraded the tight junction protein occludin, contributing to the destruction of the pulmonary epithelial barrier [ 104 ]. In the case of Alternaria alternata , serine proteases have been shown to be at least partially involved in the development of allergic asthma [ 91 ]; however, for this fungus, both the PAR2-dependent mechanism and the PAR2-independent route based on epidermal growth factor receptor (EGFR) activation were recently shown to be responsible for the immune response and cytokine production by epithelial cells; albeit, all fungal factors involved in this process still need to be characterized in detail [ 105 , 106 , 107 ]. In the case of Rhi o 1 aspartic endopeptidase produced by R. oryzae , the ability to bind IgE and to stimulate histamine release from peripheral blood mononuclear cells sensitized earlier with serum with anti-Rhi o 1 IgE antibodies was also demonstrated.…”

Section: Fungal Proteases As Allergensmentioning

confidence: 99%

More than Just Protein Degradation: The Regulatory Roles and Moonlighting Functions of Extracellular Proteases Produced by Fungi Pathogenic for Humans

Satała

Bras

Kozik

et al. 2023

JoF

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Extracellular proteases belong to the main virulence factors of pathogenic fungi. Their proteolytic activities plays a crucial role in the acquisition of nutrients from the external environment, destroying host barriers and defenses, and disrupting homeostasis in the human body, e.g., by affecting the functions of plasma proteolytic cascades, and playing sophisticated regulatory roles in various processes. Interestingly, some proteases belong to the group of moonlighting proteins, i.e., they have additional functions that contribute to successful host colonization and infection development, but they are not directly related to proteolysis. In this review, we describe examples of such multitasking of extracellular proteases that have been reported for medically important pathogenic fungi of the Candida, Aspergillus, Penicillium, Cryptococcus, Rhizopus, and Pneumocystis genera, as well as dermatophytes and selected endemic species. Additional functions of proteinases include supporting binding to host proteins, and adhesion to host cells. They also mediate self-aggregation and biofilm formation. In addition, fungal proteases affect the host immune cells and allergenicity, understood as the ability to stimulate a non-standard immune response. Finally, they play a role in the proper maintenance of cellular homeostasis. Knowledge about the multifunctionality of proteases, in addition to their canonical roles, greatly contributes to an understanding of the mechanisms of fungal pathogenicity.

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Alternaria alternata-induced airway epithelial signaling and inflammatory responses via protease-activated receptor-2 expression

Cited by 11 publications

References 51 publications

β‐Arrestin‐biased proteinase‐activated receptor‐2 antagonist C781 limits allergen‐induced airway hyperresponsiveness and inflammation

β‐Arrestin‐biased proteinase‐activated receptor‐2 antagonist C781 limits allergen‐induced airway hyperresponsiveness and inflammation

Protease allergens as initiators–regulators of allergic inflammation

More than Just Protein Degradation: The Regulatory Roles and Moonlighting Functions of Extracellular Proteases Produced by Fungi Pathogenic for Humans

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