Journal
INTERNATIONAL IMMUNOPHARMACOLOGY
Volume 101, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.intimp.2021.108325
Keywords
Microglia; Inflammatory response; Ischemic stroke; NLRP3 inflammasome
Categories
Funding
- National Natural Science Foundation of China [82171310, 81920108017, 81630028]
- Natural Science Foundation of Jiangsu Province of China [BK20170122]
- Key Research and Development Program of Jiangsu Province of China [BE2020620]
- Jiangsu Province Key Medical Discipline [ZDXKA2016020]
- Young Talent Support Program from Jiangsu Association for Science and Technology
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The novel compound JLX001 shows anti-inflammatory, antioxidative, and anti-apoptotic effects in ischemic stroke, attenuating brain damage and reducing proinflammatory cytokine expression while increasing anti-inflammatory cytokine expression. By regulating microglial polarization and NLRP3 inflammasome, JLX001 presents a promising therapeutic approach for ischemic stroke.
Ischemic stroke is a devastating disease with high morbidity and mortality rates, and the proinflammatory microglia-mediated inflammatory response directly affects stroke outcome. Previous studies have reported that JLX001, a novel compound with a structure similar to that of cyclovirobuxine D (CVB-D), exerts antiapoptotic, anti-inflammatory and antioxidative effects on ischemia-induced brain injury. However, the role of JLX001 in microglial polarization and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome regulation after ischemic stroke has not been fully investigated. In this study, we used the middle cerebral artery occlusion (MCAO) method to establish a focal cerebral ischemia model and found that JLX001 attenuated the brain infarct size and improved cerebral damage. Moreover, the expression levels of proinflammatory cytokines (interleukin [IL]-113 and tumor necrosis factor [TNF]-alpha) were significantly reduced while those of the anti-inflammatory cytokine IL-10 were increased in the JLX001-treated group. Immunofluorescence staining and flow cytometry revealed an increased number of anti-inflammatory phenotypic microglia and a reduced number of proinflammatory phenotypic microglia in JLX001-treated MCAO mice. Western blotting analysis showed that JLX001 inhibited the expression of NLRP3 and proteins related to the NLRP3 inflammasome axis in vivo. Furthermore, JLX001 reduced the number of NLRP3/Iba1 cells in ischemic penumbra tissues. Finally, mechanistic analysis revealed that JLX001 significantly inhibited the expression of proteins related to the NF-KB signaling pathway. Additionally, pyrrolidine dithiocarbamate (PDTC), an NF-KB inhibitor, ameliorated cerebral ischemia-reperfusion injury by suppressing microglial polarization towards the proinflammatory phenotype and NLRP3 activation in vivo, further suggesting that these protective effects of JLX001 were mediated by inhibition of the NF-KB signaling pathway. These results suggest that JLX001 is a promising therapeutic approach for ischemic stroke.
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