Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini
{"title":"在饮食诱发肥胖的小鼠模型中,肠胶质 NLRP3 炎症小体有助于肠道粘膜屏障的改变","authors":"Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini","doi":"10.1111/apha.14232","DOIUrl":null,"url":null,"abstract":"AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (<jats:sup>−/−</jats:sup>) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3<jats:sup>−/−</jats:sup> mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.","PeriodicalId":107,"journal":{"name":"Acta Physiologica","volume":"32 1","pages":""},"PeriodicalIF":5.6000,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet‐induced obesity\",\"authors\":\"Vanessa D'Antongiovanni, Matteo Fornai, Rocchina Colucci, Anna Nericcio, Laura Benvenuti, Clelia Di Salvo, Cristina Segnani, Clarissa Pierucci, Chiara Ippolito, Zoltan H. Nemeth, György Haskó, Nunzia Bernardini, Luca Antonioli, Carolina Pellegrini\",\"doi\":\"10.1111/apha.14232\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (<jats:sup>−/−</jats:sup>) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3<jats:sup>−/−</jats:sup> mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.\",\"PeriodicalId\":107,\"journal\":{\"name\":\"Acta Physiologica\",\"volume\":\"32 1\",\"pages\":\"\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-09-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Acta Physiologica\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/apha.14232\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHYSIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Physiologica","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/apha.14232","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
Enteric glial NLRP3 inflammasome contributes to gut mucosal barrier alterations in a mouse model of diet‐induced obesity
AimIn the present study, we investigated the involvement of NLRP3 inflammasome in the intestinal epithelial barrier (IEB) changes associated with obesity, and its role in the interplay between enteric glia and intestinal epithelial cells (IECs).MethodsWild‐type C57BL/6J and NLRP3‐KO (−/−) mice were fed with high‐fat diet (HFD) or standard diet for 8 weeks. Colonic IEB integrity and inflammasome activation were assessed. Immunolocalization of colonic mucosal GFAP‐ and NLRP3‐positive cells along with in vitro coculture experiments with enteric glial cells (EGCs) and IECs allowed to investigate the potential link between altered IEB, enteric gliosis, and NLRP3 activation.ResultsHFD mice showed increased body weight, altered IEB integrity, increased GFAP‐positive glial cells, and NLRP3 inflammasome hyperactivation. HFD‐NLRP3−/− mice showed a lower increase in body weight, an improvement in IEB integrity and an absence of enteric gliosis. Coculture experiments showed that palmitate and lipopolysaccharide contribute to IEB damage and promote enteric gliosis with consequent hyperactivation of enteric glial NLRP3/caspase‐1/IL‐1β signaling. Enteric glial‐derived IL‐1β release exacerbates the IEB alterations. Such an effect was abrogated upon incubation with anakinra (IL‐1β receptor antagonist) and with conditioned medium derived from silenced‐NLRP3 glial cells.ConclusionHFD intake elicits mucosal enteric gliotic processes characterized by a hyperactivation of NLRP3/caspase‐1/IL‐1β signaling pathway, that contributes to further exacerbate the disruption of intestinal mucosal barrier integrity. However, we cannot rule out the contribution of NLRP3 inflammasome activation from other cells, such as immune cells, in IEB alterations associated with obesity. Overall, our results suggest that enteric glial NLRP3 inflammasome might represent an interesting molecular target for the development of novel pharmacological approaches aimed at managing the enteric inflammation and intestinal mucosal dysfunctions associated with obesity.
期刊介绍:
Acta Physiologica is an important forum for the publication of high quality original research in physiology and related areas by authors from all over the world. Acta Physiologica is a leading journal in human/translational physiology while promoting all aspects of the science of physiology. The journal publishes full length original articles on important new observations as well as reviews and commentaries.