scholarly journals Blockage of NLRP3 inflammasome activation ameliorates acute inflammatory injury and long-term cognitive impairment induced by necrotizing enterocolitis in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Fangxinxing Zhu ◽  
Lingyu Wang ◽  
Zizhen Gong ◽  
Yanyan Wang ◽  
Yanhong Gao ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Survival Rate ◽  
Necrotizing Enterocolitis ◽  
Nlrp3 Inflammasome ◽  
Gastrointestinal Disease ◽  
Brain Inflammation ◽  
Neurological Dysfunction ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation

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.

scholarly journals Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain

2018 ◽  
Vol 10 (471) ◽  
pp. eaan0237 ◽  
Author(s):  
Diego F. Niño ◽  
Qinjie Zhou ◽  
Yukihiro Yamaguchi ◽  
Laura Y. Martin ◽  
Sanxia Wang ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Microglial Activation ◽  
Gastrointestinal Disease ◽  
Cognitive Impairments ◽  
High Mobility ◽  
Neurological Dysfunction ◽  
Mucosal Inflammation ◽  
Signaling Axis ◽  
The Brain

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease of the premature infant. One of the most important long-term complications observed in children who survive NEC early in life is the development of profound neurological impairments. However, the pathways leading to NEC-associated neurological impairments remain unknown, thus limiting the development of prevention strategies. We have recently shown that NEC development is dependent on the expression of the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium, whose activation by bacteria in the newborn gut leads to mucosal inflammation. Here, we hypothesized that damage-induced production of TLR4 endogenous ligands in the intestine might lead to activation of microglial cells in the brain and promote cognitive impairments. We identified a gut-brain signaling axis in an NEC mouse model in which activation of intestinal TLR4 signaling led to release of high-mobility group box 1 in the intestine that, in turn, promoted microglial activation in the brain and neurological dysfunction. We further demonstrated that an orally administered dendrimer-based nanotherapeutic approach to targeting activated microglia could prevent NEC-associated neurological dysfunction in neonatal mice. These findings shed light on the molecular pathways leading to the development of NEC-associated brain injury, provide a rationale for early removal of diseased intestine in NEC, and indicate the potential of targeted therapies that protect the developing brain in the treatment of NEC in early childhood.

scholarly journals Honokiol-Mediated Mitophagy Ameliorates Postoperative Cognitive Impairment Induced by Surgery/Sevoflurane via Inhibiting the Activation of NLRP3 Inflammasome in the Hippocampus

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ji-Shi Ye ◽  
Lei Chen ◽  
Ya-Yuan Lu ◽  
Shao-Qing Lei ◽  
Mian Peng ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Cognitive Change ◽  
Control Group ◽  
Inflammasome Activation ◽  
Mitochondrial Ros ◽  
Nlrp3 Inflammasome Activation ◽  
Postoperative Cognitive Impairment

Background. The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. Methods. In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. Results. The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. Conclusion. These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.

scholarly journals NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide

Neuroscience ◽  
2017 ◽  
Vol 343 ◽  
pp. 77-84 ◽  
Author(s):  
Wei Zhu ◽  
Feng-Sheng Cao ◽  
Jun Feng ◽  
Hua-Weng Chen ◽  
Jie-Ru Wan ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Behavioral Alterations ◽  
Nlrp3 Inflammasome Activation

scholarly journals NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 692
Author(s):  
Carrie-Anne Malinczak ◽  
Charles F. Schuler ◽  
Angela J. Duran ◽  
Andrew J. Rasky ◽  
Mohamed M. Mire ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Severe Disease ◽  
Critical Role ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Increased Risk ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

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