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Published on: June 29, 2021
Expression of proteinase-activated receptor (PAR)-2 in monocytes from allergic patients and potential molecular
Shuqing Ge1,2, Tao Li3, Qijian Yao3
1Allergy and Clinical Immunology Research Centre, the First Affiliated Hospital of Liaoning Medical University, No. 2, Section 5, Renmin Street, Guta District, Jinzhou, Liaoning, 121001, People's Republic of China.
Abstract:
Serine proteases play an important role in inflammation via PARs. However, little is known of expression levels of PARs on monocytes of allergic patients, and influence of serine proteases and PARs on TNF-α secretion from monocytes. Using quantitative real-time PCR (qPCR) and flowcytometry techniques, we observed that the expression level of PAR-2 in monocytes of patients with allergic rhinitis and asthma was increased by 42.9 and 38.2 %. It was found that trypsin, thrombin, and tryptase induced up to 200, 320, and 310 % increase in TNF-α release from monocytes at 16 h, respectively. PAR-1 agonist peptide, SFLLR-NH2, and PAR-2 agonist peptide tc-LIGRLO-NH2 provoked up to 210 and 240 % increase in release of TNF-α. Since SCH 79797, a PAR-1 antagonist, and PD98059, an inhibitor of ERK inhibited thrombin- and SFLLR-NH2-induced TNF-α release, the action of thrombin is most likely through a PAR-1- and ERK-mediated signaling mechanism. Similarly, because FSLLRN-NH2, an inhibitor of PAR-2 diminished tryptase- and tc-LIGRLO-NH2-induced TNF-α release, the action of tryptase appears PAR-2 dependent. Moreover, in vivo study showed that both recombinant cockroach major allergens Per a 1 and Per a 7 provoked upregulation of PAR-2 and PAR-1 expression on CD14+ cells in OVA-sensitized mouse peritoneum. In conclusion, increased expression of PAR-2 in monocytes of AR and asthma implicates that PAR-2 likely play a role in allergy. PAR-2- and PAR-1-mediated TNF-α release from monocytes suggests that these unique protease receptors are involved in the pathogenesis of inflammation.
Insights
Monocytes in allergic rhinitis and asthma show increased Proteinase-Activated Receptor-2 (PAR-2) expression. Serine proteases and PARs significantly increase TNF-α release, suggesting their role in allergic inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Allergy Research
Background:
- Serine proteases and Proteinase-Activated Receptors (PARs) are implicated in inflammatory processes.
- Limited data exists on PAR expression in monocytes of allergic patients and their role in TNF-α secretion.
Purpose of the Study:
- To investigate the expression levels of PARs on monocytes from allergic patients.
- To determine the influence of serine proteases and PARs on TNF-α secretion from monocytes.
- To elucidate the signaling pathways involved in protease-induced TNF-α release.
Main Methods:
- Quantitative real-time PCR (qPCR) and flow cytometry were used to assess PAR expression.
- Monocytes were stimulated with various serine proteases (trypsin, thrombin, tryptase) and PAR-specific agonists.
- Inhibition studies using PAR antagonists and signaling pathway inhibitors (e.g., ERK inhibitor) were performed.
- An in vivo study in OVA-sensitized mice assessed PAR expression on CD14+ cells.
Main Results:
- Monocytes from allergic rhinitis and asthma patients exhibited significantly increased PAR-2 expression (42.9% and 38.2%, respectively).
- Trypsin, thrombin, and tryptase induced substantial increases in TNF-α release (up to 200%, 320%, and 310%, respectively).
- PAR-1 and PAR-2 agonists also significantly elevated TNF-α release (up to 210% and 240%, respectively).
- Thrombin-induced TNF-α release was mediated via PAR-1 and ERK signaling.
- Tryptase-induced TNF-α release was dependent on PAR-2.
- Allergens Per a 1 and Per a 7 upregulated PAR-1 and PAR-2 expression in vivo.
Conclusions:
- Elevated PAR-2 expression on monocytes in allergic rhinitis and asthma suggests a role for PAR-2 in allergy pathogenesis.
- PAR-1 and PAR-2 mediated TNF-α release indicates their involvement in the inflammatory response associated with allergies.
- These findings highlight PARs as potential therapeutic targets in allergic inflammation.
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