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  • nourseothricin In summary our findings show that LPS can

    2020-01-15

    In summary, our findings show that LPS can activate CysLT2R on microglial nourseothricin to induce microglial inflammation and microglia-dependent neuronal death. Furthermore, pharmacological inhibition or knocking down of CysLT2R expression protects neurons against neurotoxicity via suppression of LPS-induced microglial responses. Based on these results, we demonstrate that the CysLT2R mediates LPS-induced microglial inflammation and consequent neurotoxicity. The CysLT2R may be a promising molecular target that modulates microglia-related neuroinflammation in neurodegenerative disorders including PD.
    Experimental procedures
    Competing interests
    Authors׳ contributions
    Acknowledgments This study was supported by the National Natural Science Foundation of China (81273491 and 81401043), the Zhejiang Provincial Natural Science Foundation (LY12H31010 and LQ13H310004).
    Introduction Leukotrienes (LTs) are potent arachidonic acid-derived mediators, acting via specific receptors that initiate signal transduction events leading to coordinated cellular responses [1]. Specific enzymes for the synthesis of LTs are present in several types of inflammatory cells and become activated during e.g. allergic or inflammatory reactions. The biosynthesis of LTs occurs according to a strict cellular selectivity; however, it is now clear that production of LTs within a tissue takes place in a more complex manner in which covalent transformations of arachidonate occur in one cell type (donor cell, e.g. polymorphonuclear leukocytes, PMNL) and then an intermediate (leukotriene A4, LTA4) is passed onto a second cell (acceptor cell, e.g. platelets, erythrocytes, endothelial cells) to complete the transformation into the biologically active cysteinyl-LTs, namely LTC4, LTD4 and LTE4. This transfer of intermediates, defined as “transcellular biosynthesis” [2] is, likely, a common event that could significantly influence the biosynthetic spectrum of active products synthesized by a tissue in response to a specific stimulus. Therefore, endothelial cells (ECs), through the interaction with circulating neutrophils could play a significant role in the local biosynthesis of significant amounts of cysteinyl-LTs during a typical inflammatory response. Results obtained in complex in vitro models of isolated and intact, PMNL-perfused, rabbit heart [3], [4], [5] and guinea-pig brain [6] support the hypothesis that transcellular biosynthesis of cysteinyl-LTs may represent a contributing pathogenic mechanism toward the development of cardiac and cerebral inflammation and edema. The cysteinyl-LTs are known to be involved in asthmatic bronchoconstriction [7], but their effects on the cardiovascular (CV) system are also becoming more and more evident [8], [9]. Cysteinyl-LTs exert potent effects on the microvasculature, where they can enhance permeability of postcapillary venules, reduce coronary blood flow, myocardial contractility and cardiac output without affecting the heart rate [10], [11], [12]. Cysteinyl-LTs exert their biological effects by activating two specific receptors, belonging to the superfamily of G protein-coupled receptors (GPCRs) i.e. CysLT1 and CysLT2 receptors [13], although the existence of additional subtypes has been proposed [14], [15]. Previous studies demonstrated that cysteinyl-LTs can trigger nourseothricin several functional responses in ECs, such as endothelium-dependent relaxation of human saphenous vein [16] or human pulmonary vein [17], increased secretion of von Willebrand factor [18] and PAF accumulation leading to neutrophil adhesion to the endothelium [19]. Besides, cysteinyl-LT-induced activation of ECs may also lead to changes in their transcriptional activity, inducing an increased expression of P-selectin [20] or of macrophage inflammatory protein-2 (MIP-2) [21], and, in cooperation with thrombin, regulation of a number of early genes resulting in a pro-inflammatory EC phenotype [22].