The activation fragment of PAR2 is elevated in serum from patients with rheumatoid arthritis and reduced in response to anti-IL6R treatment

Kalogera, Stefania; He, Yi; Bay‐Jensen, Anne‐Christine; Gantzel, Thorbjørn; Sun, Shenghua; Manon‐Jensen, Tina; Karsdal, Morten; Thudium, Christian S.

doi:10.1038/s41598-021-03346-0

Cited by 5 publications

(4 citation statements)

References 36 publications

(37 reference statements)

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“…Closely monitoring PAR2-peptide levels in a patient before and after surgery might thus allow the detection of regrowing tumors, if they become inflamed. PAR2 expression is not specific to GBM and fragments have been detected in other diseases 80 . Despite a much higher peptide coverage, we did not identify any circulating PAR2 peptides in the Meningioma control cohort.…”

Section: Par2 Abundance In Highly Individual Serum Proteomes Matches ...mentioning

confidence: 99%

Proteomic profiling of IDH-wildtype Glioblastoma Tissue and Serum uncovers prognostic Subtypes and Marker Candidates

Werner,

Schäfer,

Hennes

et al. 2024

Preprint

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Background: IDH-wildtype glioblastoma (GBM) is the most prevalent primary brain cancer with a 5-year survival rate below 10%. Despite combined treatment through extensive resection and radiochemotherapy, nine out of ten patients develop recurrences. The lack of targeted treatment options and reliable diagnostic markers for recurrent tumors remain major challenges. Methods & Aims: In this study, we present the proteomic characterization of tissue and serum from 55 initial GBM tumors and five matching recurrences, which we investigated for proteomic tumor subtypes and proteomic signatures associated with recurrence. Results: Primary tumors revealed four distinct subgroups through hierarchical clustering: a neuronal cluster with elevated mature neuron markers, an innate immunity cluster with increased protease expression, a mixed cluster, and a stem-cell cluster. Neurodevelopmental and inflammatory processes were identified as key factors influencing clustering, with proteolytic activity increasing relative to the degree of inflammation. An analysis comprising proteins with lower coverage confirmed and expanded this pattern. Patients in the neuronal cluster exhibited significantly longer survival compared to those in the stem-cell cluster. In a patient-matched differential expression analysis, five recurrent tumors displayed significantly altered protein expression compared to their primary counterparts, emphasizing the proteomic plasticity of recurrent tumors. Investigation of serum proteomes before and after surgery, using a depletion-based protocol, revealed highly patient-specific and stable proteome compositions, despite a notable increase in inflammation markers post-surgery. However, the levels of circulating proteolytic products matched to the proteolytic activity within the tissue and one fragment of proteolysis activated receptor 2 (PAR2) consistently dropped in abundance after removal of inflamed tumors. Conclusion: Overall, we describe a large proteomic GBM cohort. We identified distinct tumor subgroups, molecular patterns of recurrence, and matching proteomic patterns in the bloodstream, which may improve risk prediction for recurrent GBM.

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Section: Par2 Abundance In Highly Individual Serum Proteomes Matches ...mentioning

confidence: 99%

Proteomic profiling of IDH-wildtype Glioblastoma Tissue and Serum uncovers prognostic Subtypes and Marker Candidates

Werner,

Schäfer,

Hennes

et al. 2024

Preprint

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“…its pro-inflammatory effects, PAR-2 has also been shown to play a role in pain regulation in OA [69]. Activation of PAR-2 in sensory nerve endings has been shown to lead to the release of pain-causing substances, such as substance P and calcitonin gene-related peptide (CGRP), which can contribute to the development of joint pain in OA.…”

Section: Plos Onementioning

confidence: 99%

Evaluating the potential of Vitamin D and curcumin to alleviate inflammation and mitigate the progression of osteoarthritis through their effects on human chondrocytes: A proof-of-concept investigation

Patnaik,

Riaz,

Sivani

et al. 2023

PLoS ONE

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Osteoarthritis (OA) is a chronic degenerative joint disorder primarily affecting the elderly, characterized by a prominent inflammatory component. The long-term side effects associated with current therapeutic approaches necessitate the development of safer and more efficacious alternatives. Nutraceuticals, such as Vitamin D and curcumin, present promising therapeutic potentials due to their safety, efficacy, and cost-effectiveness. In this study, we utilized a proinflammatory human chondrocyte model of OA to assess the anti-inflammatory properties of Vitamin D and curcumin, with a particular focus on the Protease-Activated Receptor-2 (PAR-2) mediated inflammatory pathway. Employing a robust siRNA approach, we effectively modulated the expression of PAR-2 to understand its role in the inflammatory process. Our results reveal that both Vitamin D and curcumin attenuate the expression of PAR-2, leading to a reduction in the downstream proinflammatory cytokines, such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin 6 (IL-6), and Interleukin 8 (IL-8), implicated in the OA pathogenesis. Concurrently, these compounds suppressed the expression of Receptor Activator of Nuclear Factor kappa-Β Ligand (RANKL) and its receptor RANK, which are associated with PAR-2 mediated TNF-α stimulation. Additionally, Vitamin D and curcumin downregulated the expression of Interferon gamma (IFN-γ), known to elevate RANKL levels, underscoring their potential therapeutic implications in OA. This study, for the first time, provides evidence of the mitigating effect of Vitamin D and curcumin on PAR-2 mediated inflammation, employing an siRNA approach in OA. Thus, our findings pave the way for future research and the development of novel, safer, and more effective therapeutic strategies for managing OA.

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“…Being able to evaluate the activation state of the receptor, instead of its presence on the cell surface, may be a more accurate approach to evaluate the activity of this inflammatory pathway and may also function as a biomarker that could be used in asthma. A recent study showed that the small peptide liberated from the receptor when it is cleaved by activating serine proteases can be detected in human serum and its levels increase in patients with rheumatoid arthritis and responds to treatment of the disease with specific biologics (109). It will be interesting to test whether the levels of this peptide also change in asthma and whether it may be used as another biomarker for asthma severity and/or control.…”

Section: Par 2 Expression As An Asthma Biomarkermentioning

confidence: 99%

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

2022

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PAR2, a receptor activated by serine proteases, has primarily pro-inflammatory roles in the airways and may play a role in asthma pathogenesis. PAR2 exerts its effects in the lungs through activation of a variety of airway cells, but also activation of circulating immune cells. There is evidence that PAR2 expression increases in asthma and other inflammatory diseases, although the regulation of PAR2 expression is not fully understood. Here we review the available literature on the potential role of PAR2 in asthma pathogenesis and propose a model of PAR2-mediated development of allergic sensitization. We also propose, based on our previous work, that PAR2 expression on peripheral blood monocyte subsets has the potential to serve as a biomarker of asthma severity and/or control.

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The activation fragment of PAR2 is elevated in serum from patients with rheumatoid arthritis and reduced in response to anti-IL6R treatment

Cited by 5 publications

References 36 publications

Proteomic profiling of IDH-wildtype Glioblastoma Tissue and Serum uncovers prognostic Subtypes and Marker Candidates

Proteomic profiling of IDH-wildtype Glioblastoma Tissue and Serum uncovers prognostic Subtypes and Marker Candidates

Evaluating the potential of Vitamin D and curcumin to alleviate inflammation and mitigate the progression of osteoarthritis through their effects on human chondrocytes: A proof-of-concept investigation

Protease-activated receptor-2: Role in asthma pathogenesis and utility as a biomarker of disease severity

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