title: The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans.
abstract: OBJECTIVE
  NLRP3 inflammasome is known to be involved in inflammatory bowel diseases. However, it is controversial whether it is pathogenic or beneficial. This study evaluated the roles of NLRP3 inflammasome in the pathogenesis of inflammatory bowel disease in IL-10-/- mice and humans.
  
  
  METHODS
  NLRP3 inflammasome in colonic mucosa, macrophages, and colonic epithelial cells were analysed by western blotting. The NLRP3 inflammasome components were studied by sucrose density gradient fractionation, chemical cross-linking, and co-immunoprecipitation. The role of NLPR3 inflammasome in the pathogenesis of colitis was extensively evaluated in IL-10-/- mice, using a specific NLPR3 inflammasome inhibitor glyburide.
  
  
  RESULTS
  NLRP3 inflammasome was upregulated in colonic mucosa of both IL-10-/- mice and Crohn's patients. NLRP3 inflammasome activity in IL-10-/- mice was elevated prior to colitis onset; it progressively increased as disease worsened and peaked as macroscopic disease emerged. NLRP3 inflammasome was found in both intestinal epithelial cells and colonic macrophages, as a large complex with a molecular weight of ≥ 360 kDa in size. In the absence of IL-10, NLRP3 inflammasome was spontaneously active and more robustly responsive when activated by LPS and nigericin. Glyburide markedly suppressed NLRP3 inflammasome expression/activation in IL-10-/- mice, leading to not only alleviation of ongoing colitis but also prevention/delay of disease onset. Glyburide also effectively inhibited the release of proinflammatory cytokines/chemokines by mucosal explants from Crohn's patients.
  
  
  CONCLUSIONS
  Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10-/- mice and humans. Glyburide, an FDA-approved drug, may have great potential in the management of inflammatory bowel diseases.
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Endocrinology, Renji Hospital, Shanghai Jiaotong University, Minhang Qu, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Department of Internal Medicine & Geriatrics, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Ye
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Jin
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yang
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Joosse
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lazarev
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Brant
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Bashar
authors.initials: B
authors.lastname: Safar
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Marohn
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Mezey
authors.affiliation: Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Xuhang
authors.initials: X
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D046728:Colitis, Microscopic / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D009550:Nigericin / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D016207:Cytokines; D007004:Hypoglycemic Agents; C556062:IL10 protein, mouse; D058847:Inflammasomes; D008070:Lipopolysaccharides; C529636:NALP1 protein, mouse; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; C498534:Pycard protein, mouse; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D020170:Caspase 1; D009550:Nigericin; D005905:Glyburide
keywords: IL-10; NLRP3 inflammasome; inflammatory bowel diseases [IBD]