Fangxinxing Zhu1,2,3, Lingyu Wang1,2,3, Zizhen Gong1,2,3, Yanyan Wang1,2,3, Yanhong Gao4, Wei Cai5,6,7, Jin Wu8,9,10. 1. Department of Pediatric Surgery, Xinhua hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. 2. Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. 3. Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. 4. Department of Geriatrics, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. 5. Department of Pediatric Surgery, Xinhua hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. caiw204@sjtu.edu.cn. 6. Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. caiw204@sjtu.edu.cn. 7. Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. caiw204@sjtu.edu.cn. 8. Department of Pediatric Surgery, Xinhua hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. wujin@xinhuamed.com.cn. 9. Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. wujin@xinhuamed.com.cn. 10. Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. wujin@xinhuamed.com.cn.
Abstract
BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease in premature neonates with high mortality and morbidity, while the underlining mechanism of intestinal injury and profound neurological dysfunction remains unclear. Here, we aimed to investigate the involvement of NLPR3 inflammasome activation in NEC-related enterocolitis and neuroinflammation, especially long-term cognitive impairment, meanwhile, explore the protective effect of NLRP3 inhibitor MCC950 on NEC in mice. METHODS: NLRP3 inflammasome activation in the intestine and brain was assessed in the NEC mouse model, and NLRP3 inhibitor MCC950 was administrated during the development of NEC. Survival rate, histopathological injury of the intestine and brain, and expression of mature IL-1β and other pro-inflammatory cytokines were analyzed. Long-term cognitive impairment was evaluated by behavioral test. RESULTS: The expression of NLRP3 and mature IL-1β in the intestine and brain was greatly upregulated in NEC mice compared to the controls. MCC950 treatment efficiently improved NEC survival rate, reduced intestinal and brain inflammation, and ameliorated the severity of pathological damage in both organs. Additionally, in vivo blockage of NLRP3 inflammasome with MCC950 in early life of NEC pups potently protected against NEC-associated long-term cognitive impairment. CONCLUSIONS: Our findings suggest that NLRP3 inflammasome activation participates in NEC-induced intestinal and brain injury, and early intervention with NLRP3 inhibitor may provide beneficial therapeutic effect on NEC infants.
BACKGROUND: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal disease in premature neonates with high mortality and morbidity, while the underlining mechanism of intestinal injury and profound neurological dysfunction remains unclear. Here, we aimed to investigate the involvement of NLPR3 inflammasome activation in NEC-related enterocolitis and neuroinflammation, especially long-term cognitive impairment, meanwhile, explore the protective effect of NLRP3 inhibitor MCC950 on NEC in mice. METHODS: NLRP3 inflammasome activation in the intestine and brain was assessed in the NEC mouse model, and NLRP3 inhibitor MCC950 was administrated during the development of NEC. Survival rate, histopathological injury of the intestine and brain, and expression of mature IL-1β and other pro-inflammatory cytokines were analyzed. Long-term cognitive impairment was evaluated by behavioral test. RESULTS: The expression of NLRP3 and mature IL-1β in the intestine and brain was greatly upregulated in NEC mice compared to the controls. MCC950 treatment efficiently improved NEC survival rate, reduced intestinal and brain inflammation, and ameliorated the severity of pathological damage in both organs. Additionally, in vivo blockage of NLRP3 inflammasome with MCC950 in early life of NEC pups potently protected against NEC-associated long-term cognitive impairment. CONCLUSIONS: Our findings suggest that NLRP3 inflammasome activation participates in NEC-induced intestinal and brain injury, and early intervention with NLRP3 inhibitor may provide beneficial therapeutic effect on NEC infants.
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