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  • Cysteinyl leukotrienes CysLTs are potent inflammatory


    Cysteinyl leukotrienes (CysLTs) are potent inflammatory mediators closely associated with cerebral ischemic injury. CysLTs induce inflammatory responses mediated by at least two different CysLT receptors (CysLT1R and CysLT2R) (Bäck et al., 2011, Singh et al., 2010). It has been reported that the CysLT1R plays important regulatory roles in cerebral ischemic injury, and CysLT1R selective antagonists pranlukast and montelukast have protective effects on cerebral ischemia (Fang et al., 2006, Yu et al., 2005, Yu et al., 2014, Zhang and Wei, 2003, Zhang et al., 2013, Zhao et al., 2011b). Compared to CysLT1Rs, the roles of CysLT2Rs remain largely unexplored due to the lack of selective CysLT2R antagonists (other than the nonselective CysLT1R/CysLT2R antagonist Bay U9773). Recently, HAMI 3379 has been reported to be a selective antagonist for CysLT2R (Wunder et al., 2010). Several recent studies have found that CysLT2R is involved in postischemic inflammation and gap27 injury in focal cerebral ischemia of rat as well as in ischemic-like injury induced by oxygen-glucose deprivation (OGD) in vitro, and the antagonism of CysLT2R by HAMI 3379 protects neurons against ischemic brain injury (Shi et al., 2012, Shi et al., 2015, Zhao et al., 2011a, Zhang et al., 2013). However, whether CysLT2Rs mediate PD-associated microglial inflammation and microglia-dependent neurotoxicity remains unclear. In this study, we determined the regulatory role of CysLT2R in microglial inflammation and subsequent neurotoxicity in an in vitro lipopolysaccharide (LPS)-induced inflammation model of PD (Chinta et al., 2013, Hosoi et al., 2014, Svensson et al., 2010). In addition, we also examined the neuroprotective effects of CysLT2R selective antagonist and RNA interference on PD-associated neuroinflammation caused by LPS.
    Discussion In the present study, we revealed that stimulation of BV-2 cells by LPS resulted in a strong inflammatory reaction and neural PC12 cell death, and these responses were mediated by activation of the CysLT2R. Targeting CysLT2Rs on BV-2 cells offered a means of preserving PC12 cells from neurotoxicity by inhibiting LPS-induced microglial inflammation. A major finding of this study is that the CysLT2R mediated LPS-induced microglial inflammation in BV-2 cells. This notion is supported by the observations in at least two ways. On one hand, CysLT2R expression was increased by LPS in BV-2 cells in a time- and dose-dependent manner, suggesting CysLT2R activation in LPS-stimulated BV-2 cells. On the other hand, LPS-induced microglial responses, phagocytosis and release of proinflammatory cytokines, were significantly inhibited by HAMI 3379, a selective CysLT2R antagonist, and specific RNA interference of CysLT2R in BV-2 cells. These results indicate that LPS induces microglial inflammation by activating the CysLT2R. Currently, many studies emphasize the critical role of CysLT2R in regulating cardiovascular and cerebral injury following ischemia (Ni et al., 2014, Qi et al., 2011, Shi et al., 2012, Shi et al., 2015, Wunder et al., 2010, Zhang et al., 2013, Zhao et al., 2011a). In human embryonic kidney 293 cells, CysLT2R mediates CysLTR agonist leukotriene C4 and leukotriene D4-induced IL-8 production by extracellular signal-regulated protein kinases 1 and 2 (ERK1/2)-early growth response-1 signaling pathway (Lin et al., 2014). The CysLT2R knockout mice were reported to develop less severe colitis as well as retinopathy (Barajas-Espinosa et al., 2011, Barajas-Espinosa et al., 2012). CysLT2R is involved in the dextran sulfate sodium-induced progression of colitis, particularly by increasing colonic edema, submucosal venule permeability, TNF-α production, and by potentially altering dorsal root ganglia neuron excitability (Barajas-Espinosa et al., 2011). CysLT2R also mediates retinal edema and pathological neovascularization in a murine model of oxygen-induced retinopathy (Barajas-Espinosa et al., 2012). Our findings reveal a novel regulatory role of CysLT2R in LPS-induced microglial inflammation.