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Basic concepts on melanocyte biology
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Keratinocytes, for their part, actively participate in regulating the process of melanosome uptake. The expression of specific receptors on keratinocytes, but not on melanocytes, positively controls melanosome internalization. Among them, the G-protein-coupled protease-activated receptor 2 (PAR-2) is decisive in melanosome uptake by stimulating the process of phagocytosis. PAR-2 receptors are activated by proteolytic cleavage of their extracellular N-terminal domain via serine proteases. The cleavage discloses tethered ligands that bind the receptor, thus inducing its activation. Once activated, PAR-2 increases melanosome internalization by a Rho-dependent mechanism.23,24 PAR-2 expression and activity are upregulated following UV25 and are also correlated with skin color, showing more elevated levels with respect to lightly pigmented skin.26 Melanosome transfer is also stimulated by the expression and activation of the keratinocyte growth factor receptor (KGFR) in early differentiated keratinocytes, where the levels of the receptor are increased. KGFR directly promotes the phagocytic process27,28 (Figure 1.7).
Pathophysiology of asthma
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
Allergens and/or other environmental agents with or without protease activity and different pathogens may elicit severe disease early or late in life (Figure 5.10). Therapies directed against various arms of the type 2 immune response based on the patient's inflammatory response and other characteristics have shown promise in recent clinical trials. While an IFN-γ (Th1/type 1) immune response has been identified in different patient cohorts, no therapy has yet been directed against this arm of the immune response. IFN-γ can inhibit SLPI expression from airway epithelial cells. SLPI is a protease inhibitor secreted by airway epithelial cells that inhibits proteases present in different cell types (mast cells, neutrophils) and infectious agents. Protease-activated PAR2 on airway smooth muscle cells has been implicated in AHR in animal studies. IFN-γ and low levels of the type 2 cytokine IL-13 can synergize to induce nitro-oxidative stress in airway epithelial cells. Future studies will determine the potential role of ILC2s and ILC2-activating cytokines such as IL-33 in severe asthma. Nasal polyps are also encountered in severe asthma, usually in late-onset disease, and crosstalk between the nasal mucosa and the airways may occur due to leakage of cytokines such as IL-5 from the local site (nose) of inflammation.
Host–Biofilm Interactions at Mucosal Surfaces and Implications in Human Health
Published in Chaminda Jayampath Seneviratne, Microbial Biofilms, 2017
Nityasri Venkiteswaran, Kassapa Ellepola, Chaminda Jayampath Seneviratne, Yuan Kun Lee, Kia Joo Puan, Siew Cheng Wong
Elastase LasB is an important extracellular virulence factor that regulates the inflammatory response during biofilm formation. Bacterial elastase has been shown to inactivate and degrade LL-37 [172]. The lasB deletion mutant (ΔlasB) displayed significantly decreased bacterial attachment, microcolony formation, extracellular matrix production and biofilm formation [173]. LasB cleaves host protease-activated receptors PAR2 in respiratory epithelial cells [174]. PAR2 signalling is known to regulate host inflammatory responses, particularly in the lung. Recent studies have demonstrated that the loss of PAR2 on neutrophils significantly decreased phagocytic uptake of P. aeruginosa, whereas activation of PAR2 caused recruitment of phagocytic machinery such as MAP kinases, Rho-Rac GTPases and actin, probably by acting as a direct phagocytic receptor [175,176]. Hence, the expression of elastase by virulent strains of P. aeruginosa could potentially modulate both inflammatory responses and phagocytosis through PAR2 inhibition during chronic biofilm formation.
PAR2 Overexpression is Involved in the Occurrence of Hyperoxygen-Induced Bronchopulmonary Dysplasia in Rats
Published in Fetal and Pediatric Pathology, 2023
Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in premature infants with high mortality and complication rates that seriously affects the quality of life in later stages. The use of postnatal pulmonary surfactant and mechanically assisted ventilation improves the survival rate of premature infants, but long-term or inappropriate oxygen use can increase the frequency of BPD [1]. The pathogenesis of BPD remains unclear, but inflammation has been shown to be involved in its occurrence. Protease activated receptor-2 (PAR2) is a 7-time transmembrane G-protein coupled receptor, which is involved in the occurrence of a variety of lung diseases, such as lung inflammation and bronchial asthma, and is a driver of inflammatory response [2–4]. Activated PAR2 plays a pro-inflammatory role through a variety of signaling pathways. this study investigated the changes in the expression of PAR2, p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B (NF-κB), and interleukin-18 (IL-18) in the lung tissues of hyperoxia-induced rat BPD models. The main aim of the study was to provide new insights into the pathogenesis of premature BPD to help develop preventative measures.
Coagulation factor V is a marker of tumor-infiltrating immune cells in breast cancer
Published in OncoImmunology, 2020
Mari Tinholt, Benedicte Stavik, Xavier Tekpli, Øystein Garred, Elin Borgen, Vessela Kristensen, Kristine Kleivi Sahlberg, Per Morten Sandset, Nina Iversen
The presence of cancer is commonly associated with coagulation abnormalities, resulting in a several-fold increased risk of thrombosis in cancer patients compared to the general population.1,2 Moreover, growing experimental evidences support an association between coagulation and tumor progression. A deeper understanding of the biological aspects connecting coagulation and cancer opens for the development of novel treatment strategies that may reduce both the tumor burden and the risk of thrombosis. Components of the tissue factor (TF) pathway (TF, FVIIa, FXa) have increasingly been shown to promote tumor progression and metastasis, mainly through activation of protease activated receptor 2 (PAR2) 3 The functional role of factor (F) V in cancer, however, has not yet been characterized.
Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation
Published in Islets, 2018
Seung-Hee Lee, Ergeng Hao, David Scharp, Fred Levine
Using a candidate approach focused on exocrine enzymes released by the exocrine cell destruction that occurs during pancreatitis, we identified the positively activating factor as an atypical G-protein coupled receptor (GPCR) called the Protease-Activated Receptor 2 (PAR2).9 PAR2 was necessary and sufficient to induce α− to β−cell transdifferentiation in the setting of profound β−cell deficiency.9 The essential role in islet cell transdifferentiation of PAR2, which is activated by cleavage of an N-terminal fragment of PAR2 by the exocrine enzyme trypsin,10 explained why pancreatitis, where there is ectopic release of exocrine enzymes, is so effective at stimulating transdifferentiation. However, it did not explain how the presence of β−cells inhibited transdifferentiation even when PAR2 was activated by a pharmacological agonist.9