Crucial Role For The NLRP3 Inflammasome In Irradiation-induced Cognitive Impairment In Mice

Objective: To investigate the role of NLRP3 inflammasome in cognitive dysfunction induced by irradiation in mice.Methods: Sixty Kunming mice were randomly divided into control group(Control group),irradiation group(IR group),irradiation + MCC950 group(IR + MCC950 group);IR group and IR + MCC950 group mice were given a single 137Cs-γ-ray whole body irradiation at 4Gy total dose.35 days later,short-term novelty objective recognition test(short-term NORT),and long-term novelty objective recognition test(long-term NORT),novelty place recognition test(NPRT)and social recognition test were used to detect the cognitive function of mice in each group;Immunohistochemical assay was used to detect the expression of NeuN in the hippocampus;RT-PCR was used to detect the expression of hippocampal NLRP3,ASC,Caspase-1,INOS,CXCL10,Arg1,CD206 and CD16 mRNA expression;Western blot was used to detect the expression of NLRP3,ASC,Caspase-1,CD68,IL-1β,IL-18,BAX,PARP1 and Caspase-3 in the hippocampus.Results: 1.Compared with the Control group,the IR group showed significantly reduced discrimination radio in the short-term NORT(P<0.05),long-term NORT(P<0.05),NOPT(P<0.05)and social recognition test(P<0.05);2.Compared with the Control group,the IR group showed significantly increased mRNA level of NLRP3 and Caspase-1 in the hippocampus(P <0.05),the IR group showed significantly increased protein level of NLRP3,Caspase-1,IL-1β and IL-18(P <0.05).No difference in the protein and mRNA expression of ASC between the two group(P> 0.05);3.Compared with IR group,the IR + MCC950 group showed significantly down-regulated expression of NLRP3,Caspase-1,IL-1β and IL-18 protein levels in the hippocampus(P <0.05),while there were no difference in the protein expression of ASC between the three groups(P> 0.05);4.Compared with the IR group,the IR + MCC950 group showed significantly increased discrimination radio of short-term NORT(P<0.05),long-term NORT(P<0.05),NOPT(P<0.05)and social recognition test(P<0.05);5.Compared with the IR group,the IR+ MCC950 group showed down-regulated protein expression of CD68 in the hippocampus(P <0.01),the mRNA level of M1 microglial markers,such as CD16,INOS,CXCL10 were significantly decreased in IR group(P <0.05).No difference in the expression of M2 microglial markers,such as Arg1,CD206 were found between the three groups(P> 0.05);6.Compared with the IR group,the IR + MCC950 group showed significantly increased optical density value of the mature neurons marker NeuN in hippocampal(P <0.05);7.Compared with the IR group,the IR + MCC950 group showed significantly reduced expression of pro-apoptosis-related proteins BAX,PARP1 and Caspase-3 in the hippocampus(P < 0.05).Conclusions: Irradiation induced cognitive dysfunction in mice might be due to the activation of hippocampal NLRP3 inflammasome that induces M1 polarization of microglia,which exacerbates the release of inflammatory factors and leads to neuronal apoptosis.