Cysteinyl Leukotriene Receptor 2 is Involved in Inflammation and Neuronal Damage by Mediating Microglia M1/M2 Polarization through NF-κB Pathway.

Microglia activation plays a key role in regulating inflammatory and immune reaction during cerebral ischemia and it exerts pro-inflammatory or anti-inflammatory effect depending on M/M polarization phenotype. Cysteinyl leukotriene 2 receptor (CysLTR) is a potent inflammatory mediator receptor, and involved in cerebral ischemic injury, but the mechanism of CysLTR regulating inflammation and neuron damage remains unclear. Here, we found that LPS and CysLTR agonist NMLTC significantly increased microglia proliferation and phagocytosis, up-regulated the mRNA expression of M polarization markers (IL-1β, TNF-α, IFN-γ, CD86 and iNOS), down-regulated the expression of M polarization markers (Arg-1, CD206, TGF-β, IL-10, Ym-1) and increased the release of IL-1β and TNF-α. CysLTR selective antagonist HAMI3379 could antagonize these effects. IL-4 significantly up-regulated the mRNA expression of M polarization markers, and HAMI3379 further increased IL-4-induced up-regulation of M polarization markers expression. Additionally, LPS and NMLTC stimulated NF-κB p50 and p65 proteins expression, and promoted p50 transfer to the nucleus. Pre-treatment with HAMI3379 and NF-κB signaling inhibitor Bay 11-7082 could reverse the up-regulation of p50 and p65 proteins expression, and inhibited p50 transfer to the nucleus. The conditional medium of BV-2 cells contained HAMI3379 could inhibit SH-SY5Y cells apoptosis induced by LPS and NMLTC. These results were further confirmed in primary microglia. The findings indicate that CysLTR was involved in inflammation and neuronal damage by inducing the activation of microglia M1 polarization and NF-κB pathway, inhibiting microglia M1 polarization and promoting microglia polarization toward M2 phenotype which may exerts neuroprotective effects, and targeting CysLTR may be a new therapeutic strategy against cerebral ischemia stroke.