Protease-Activated Receptor 2: Are Common Functions in Glial and Immune Cells Linked to Inflammation-Related CNS Disorders?

Bushell, Trevor J.; Cunningham, Margaret; McIntosh, Kathryn; Moudio, Serge; Plevin, Robin

doi:10.2174/1389450117666151209115232

Cited by 17 publications

(12 citation statements)

References 116 publications

(162 reference statements)

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“…F2R-Like Trypsin Receptor 1 (F2RL1), also called protease-activated receptor 2 (PAR2), is a G-protein-coupled receptor that mediates cellular responses via the activation of heteromeric G-proteins [68]. F2RL1 is expressed in most immune cells, such as neutrophils [69], eosinophils [70], monocytes [71], macrophages [72], DCs [72], mast cells [73], and T cells [74, 75]. In the skin, F2RL1 is mainly expressed in keratinocytes [76].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo

Deng

Wei

Zou

et al. 2019

Oxidative Medicine and Cellular Longevity

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Activated CD8+ T cells play important roles in the pathogenesis of vitiligo. However, driving factors about the activation and migration of CD8+ T cells remain obscure. In this study, we aim to identify differentially expressed genes (DEGs) and uncover potential factors that drive the disease in melanocyte-specific CD8+ T cells in vitiligo. A total of 1147 DEGs were found through transcriptome sequencing in CD8+ T cells from lesional skin of vitiligo patients and normal controls. Based on KEGG pathway enrichment analysis and PPI, 16 upregulated and 23 downregulated genes were identified. Ultimately, 3 genes were figured out after RT-qPCR verification. The mRNA and protein expression levels of PIK3CB, HIF-1α, and F2RL1 were all elevated in CD8+ T cells from peripheral blood in vitiligo. HIF-1α and PIK3CB were significantly increased in lesional skin of vitiligo. Two CpG sites of the HIF-1α promoter were hypomethylated in vitiligo CD8+ T cells. In conclusion, HIF-1α, F2RL1, and PIK3CB may act as novel drivers for vitiligo, which are all closely associated with reactive oxygen species and possibly contribute to the activation and/or migration of melanocyte-specific CD8+ T cells in vitiligo. In addition, we uncovered a potential role for DNA hypomethylation of HIF-1α in CD8+ T cells of vitiligo.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo

Deng

Wei

Zou

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Whilst these molecules provided lead compounds for the development of antagonists, for example in arthritis, other conditions such as those of the CNS suggest value in agonist development due to PAR2 dependent neuroprotective activity [47]. Thus, several studies have focussed on the development of PAR2 peptide agonists with the aim of creating more drug-like modulators.…”

Section: Par2 Agonists As a Template For Antagonist Developmentmentioning

confidence: 99%

The development of proteinase-activated receptor-2 modulators and the challenges involved

McIntosh

Cunningham

Bushell

et al. 2020

Biochemical Society Transactions

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Protease-activated receptor-2 (PAR2) has been extensively studied since its discovery in the mid-1990. Despite the advances in understanding PAR2 pharmacology, it has taken almost 25 years for the first inhibitor to reach clinical trials, and so far, no PAR2 antagonist has been approved for human use. Research has employed classical approaches to develop a wide array of PAR2 agonists and antagonists, consisting of peptides, peptoids and antibodies to name a few, with a surge in patent applications over this period. Recent breakthroughs in PAR2 structure determination has provided a unique insight into proposed PAR2 ligand binding sites. Publication of the first crystal structures of PAR2 resolved in complex with two novel non-peptide small molecule antagonists (AZ8838 and AZ3451) revealed two distinct binding pockets, originally presumed to be allosteric sites, with a PAR2 antibody (Fab3949) used to block tethered ligand engagement with the peptide-binding domain of the receptor. Further studies have proposed orthosteric site occupancy for AZ8838 as a competitive antagonist. One company has taken the first PAR2 antibody (MEDI0618) into phase I clinical trial (NCT04198558). While this first-in-human trial is at the early stages of the assessment of safety, other research into the structural characterisation of PAR2 is still ongoing in an attempt to identify new ways to target receptor activity. This review will focus on the development of novel PAR2 modulators developed to date, with an emphasis placed upon the advances made in the pharmacological targeting of PAR2 activity as a strategy to limit chronic inflammatory disease.

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“…Cell-cell communication via proteases has been documented in the brain (Bushell, Cunningham, McIntosh, Moudio, & Plevin, 2016;Meins et al, 2001;Monard, 1988;Niclou, Suidan, Pavlik, Vejsada, & Monard, 1998;Vance et al, 2015). A possible role for thrombin as an additional help-me signal, joining other putative signaling mechanisms such as LCN2, has recently been published (Xing et al, 2014;Xing & Lo, 2017).…”

Section: F I G U R E 4 Legend On Next Pagementioning

confidence: 99%

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Rajput

Lamb

Kothari

et al. 2019

Glia

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Astrocytes protect neurons during cerebral injury through several postulated mechanisms. Recent therapeutic attention has focused on enhancing or augmenting the neuroprotective actions of astrocytes but in some instances astrocytes can assume a neurotoxic phenotype. The signaling mechanisms that drive astrocytes toward a protective versus toxic phenotype are not fully known but cell–cell signaling via proteases acting on cell‐specific receptors underlies critical mechanistic steps in neurodevelopment and disease. The protease activated receptor (PAR), resides in multiple brain cell types, and most PARs are found on astrocytes. We asked whether neuron‐generated thrombin constituted an important astrocyte activation signal because our previous studies have shown that neurons contain prothrombin gene and transcribed protein. We used neuron and astrocyte mono‐cell cultures exposed to oxygen‐glucose deprivation and a model of middle cerebral artery occlusion. We found that ischemic neurons secrete thrombin into culture media, which leads to astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin. Media from prothrombin‐deficient neurons failed to activate astrocytes and adding thrombin to such media restored activation. Astrocytes lacking PAR1 did not respond to neuron‐generated thrombin. Induced astrocyte activation was antagonized dose‐dependently with thrombin inhibitors or PAR1 antagonists. Ischemia‐induced astrocyte activation in vivo was inhibited after neuronal prothrombin knockout, resulting in larger strokes. Restoring prothrombin to neurons with a lentiviral gene vector restored astrocyte activation and reduced stroke damage. We conclude that neuron‐generated thrombin, released during ischemia, acts via PAR1 and may cause astrocyte activation and paracrine neuroprotection.

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Protease-Activated Receptor 2: Are Common Functions in Glial and Immune Cells Linked to Inflammation-Related CNS Disorders?

Cited by 17 publications

References 116 publications

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo

The development of proteinase-activated receptor-2 modulators and the challenges involved

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

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