Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain

Zhao, Peishen; Lieu, Tina Marie; Barlow, Νicholas; Sostegni, Silvia; Haerteis, Silke; Korbmacher, Christoph; Liedtke, Wolfgang; Jiménez-Vargas, Nestor N.; Vanner, Stephen; Bunnett, Nigel W.

doi:10.1074/jbc.m115.642736

Cited by 147 publications

(154 citation statements)

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“…Other proteases, including cathepsin S and elastase, are biased agonists that cleave PAR 2 at distinct sites to induce coupling to G␣ s but not G␣ q or ␤-arrestins (23)(24)(25). Cathepsin S-and elastase-activated PAR 2 cannot be reactivated by proteolysis, but the cleaved receptors remain at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…PAR 2 activates PKD in nociceptors (27) but with unknown functional relevance. Because PAR 2 -activating proteases induce hyperexcitability of nociceptors (23,24), we investigated whether PKD mediates sustained excitability to proteases. To examine excitability, we made patch clamp recordings from small diameter neurons of mouse dorsal root ganglia.…”

Section: Pkd Mediates Sustained Protease-induced Excitability Ofmentioning

confidence: 99%

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Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Jensen

Zhao

Jiménez-Vargas

et al. 2016

Journal of Biological Chemistry

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Agonist-evoked endocytosis of G protein-coupled receptors has been extensively studied. The mechanisms by which agonists stimulate mobilization and plasma membrane translocation of G protein-coupled receptors from intracellular stores are unexplored. Protease-activated receptor-2 (PAR 2 ) traffics to lysosomes, and sustained protease signaling requires mobilization and plasma membrane trafficking of PAR 2 from Golgi stores. We evaluated the contribution of protein kinase D (PKD) and G␤␥ to this process. In HEK293 and KNRK cells, the PAR 2 agonists trypsin and 2-furoyl-LIGRLO-NH 2 activated PKD in the Golgi apparatus, where PKD regulates protein trafficking. PAR 2 activation induced translocation of G␤␥, a PKD activator, to the Golgi apparatus, determined by bioluminescence resonance energy transfer between G␥-Venus and giantin-Rluc8. Inhibitors of PKD (CRT0066101) and G␤␥ (gallein) prevented PAR 2 -stimulated activation of PKD. CRT0066101, PKD1 siRNA, and gallein all inhibited recovery of PAR 2 -evoked Ca 2؉ signaling. PAR 2 with a photoconvertible Kaede tag was expressed in KNRK cells to examine receptor translocation from the Golgi apparatus to the plasma membrane. Irradiation of the Golgi region (405 nm) induced green-red photo-conversion of PAR 2 -Kaede. Trypsin depleted PAR 2 -Kaede from the Golgi apparatus and repleted PAR 2 -Kaede at the plasma membrane. CRT0066101 inhibited PAR 2 -Kaede translocation to the plasma membrane. CRT0066101 also inhibited sustained protease signaling to colonocytes and nociceptive neurons that naturally express PAR 2 and mediate protease-evoked inflammation and nociception. Our results reveal a major role for PKD and G␤␥ in agonist-evoked mobilization of intracellular PAR 2 stores that is required for sustained signaling by extracellular proteases.

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Section: Discussionmentioning

confidence: 99%

Section: Pkd Mediates Sustained Protease-induced Excitability Ofmentioning

confidence: 99%

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Jensen

Zhao

Jiménez-Vargas

et al. 2016

Journal of Biological Chemistry

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“…21 To remove debris, digested cell suspensions were centrifuged on 30% Percoll (Sigma–Aldrich). After washing, the cell pellet was resuspended in L-15 Lebovitz medium (Thermo Fisher Scientific) with antibiotic/antimycotic solution (0.1%), and the cells were plated on glass bottom dishes that had been coated with poly-ornithine and laminin.…”

Section: Methodsmentioning

confidence: 99%

Prostanoid-dependent spontaneous pain and PAR₂-dependent mechanical allodynia following oral mucosal trauma

et al. 2017

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During dental treatments, intraoral appliances frequently induce traumatic ulcers in the oral mucosa. Such mucosal injury-induced mucositis leads to severe pain, resulting in poor quality of life and decreased cooperation in the therapy. To elucidate mucosal pain mechanisms, we developed a new rat model of intraoral wire-induced mucositis and investigated pain mechanisms using our proprietary assay system for conscious rats. A thick metal wire was installed in the rats between the inferior incisors for one day. In the mucosa of the mandibular labial fornix region, which was touched with a free end of the wire, traumatic ulcer and submucosal abscess were induced on day 1. The ulcer was quickly cured until next day and abscess formation was gradually disappeared until five days. Spontaneous nociceptive behavior was induced on day 1 only, and mechanical allodynia persisted over day 3. Antibiotic pretreatment did not affect pain induction. Spontaneous nociceptive behavior was sensitive to indomethacin (cyclooxygenase inhibitor), ONO-8711 (prostanoid receptor EP1 antagonist), SB-366791, and HC-030031 (TRPV1 and TRPA1 antagonists, respectively). Prostaglandin E2 and 15-deoxyΔ12,14-prostaglandin J2 were upregulated only on day 1. In contrast, mechanical allodynia was sensitive to FSLLRY-NH2 (protease-activated receptor PAR2 antagonist) and RN-1734 (TRPV4 antagonist). Neutrophil elastase, which is known as a biased agonist for PAR2, was upregulated on days 1 to 2. These results suggest that prostanoids and PAR2 activation elicit TRPV1- and TRPA1-mediated spontaneous pain and TRPV4-mediated mechanical allodynia, respectively, independently of bacterial infection, following oral mucosal trauma. The pathophysiological pain mechanism suggests effective analgesic approaches for dental patients suffering from mucosal trauma-induced pain.

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“…P38/ERK is activated in microglia following nerve injury, leading to their release of prostaglandins and IL-1β within the spinal cord (9, 12). Inflammatory neutrophils contribute to pain by release of neutrophil elastase, which activates protease activated receptor-2 (PAR2) on neurons (13). T cells also contribute to chronic pain by infiltrating the DRG and release of leukocyte elastase (14).…”

Section: Introductionmentioning

confidence: 99%

Neuro-immune interactions in inflammation and host defense: Implications for transplantation

Chavan

Chiu

2018

American Journal of Transplantation

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Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine.

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Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain

Cited by 147 publications

References 64 publications

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Prostanoid-dependent spontaneous pain and PAR₂-dependent mechanical allodynia following oral mucosal trauma

Neuro-immune interactions in inflammation and host defense: Implications for transplantation

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Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain

Cited by 147 publications

References 64 publications

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Protein Kinase D and Gβγ Subunits Mediate Agonist-evoked Translocation of Protease-activated Receptor-2 from the Golgi Apparatus to the Plasma Membrane

Prostanoid-dependent spontaneous pain and PAR2-dependent mechanical allodynia following oral mucosal trauma

Neuro-immune interactions in inflammation and host defense: Implications for transplantation

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Product

Resources

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Prostanoid-dependent spontaneous pain and PAR₂-dependent mechanical allodynia following oral mucosal trauma