ChemR23 activation attenuates cognitive impairment in chronic cerebral hypoperfusion via inhibiting NLRP3 inflammasome-induced neuronal pyroptosis

Background: Neuroinflammation plays critical roles in vascular dementia (VaD), the second leading cause of dementia which can be induced by chronic cerebral hypoperfusion (CCH). NLRP3 inflammasome-induced pyroptosis, the inflammatory programmed cell death has been reported to contribute to the development of VaD [1]. ChemR23 is a G protein coupled receptor that has emerging roles in regulating inflammation. However, the role of ChemR23 signaling in NLRP3 inflammasome-induced pyroptosis in CCH remains elusive. Methods: Permanent bilateral common carotid artery occlusion (BCCAO) surgery was performed in rats to establish the CCH model. Eight weeks after the surgery, the rats were intraperitoneally injected with Resolvin E1 (RvE1) or chemerin-9 (C-9) every other day for 4 weeks. Besides, SH-SY5Y cells with hypoglycemic and hypoxic stimulation were adopted to mimic CCH injury in vitro. Behavioral test was applied to access cognitive impairment. Histological and immunofluorescent staining, RNA sequencing analysis, western blot, enzyme-linked immunosorbent assay, transmission electron microscope, LDH activity assay, flow cytometry and scanning electron microscope were conducted to evaluate neuronal damage and explore the possible mechanisms in vivo and in vitro. Results: : Here, we found that the levels of ChemR23 expression were decreased from the 8th week after BCCAO, accompanied by significant cognitive impairment. Further analysis revealed that CCH induced neuronal damage, synaptic injury and NLRP3-related pyroptosis activation in hippocampal neurons. However, pharmacologic activation of ChemR23 with RvE1 or C-9 counteracted these changes. Moreover, In vitro experiments showed that manipulating ChemR23 expression markedly regulated NLRP3 inflammasome-induced neuronal pyroptosis through PI3K/AKT/Nrf2 signaling in SH-SY5Y cells under hypoglycemic and hypoxic condition. Conclusions: Our data demonstrated that ChemR23 activation inhibits NLRP3 inflammasome-induced neuronal pyroptosis and improves the cognitive function via PI3K/AKT/Nrf2 signaling pathway in CCH models. ChemR23 may serve as a potential novel therapeutic target to treat CCH-induced cognitive impairment.