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| 標題: | The ATP-P2X(7) Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
| 作者: | Liu, Ya-Hui
Chang, Yung-Chi
Chen, Liang-Kuei
Su, Po-An
Ko, Wen-Chien
Tsai, Yau-Sheng
Chen, Yi-Hsuan
Lai, Hsin-Chih
Wu, Cheng-Yeu
Hung, Yuan-Pin
Tsai, Pei-Jane |
| 貢獻者: | Natl Cheng Kung Univ, Dept Med Lab Sci & Biotechnol, Med Coll
Natl Cheng Kung Univ Hosp, Dept Pathol
Chi Mei Med Ctr, Div Infect Dis
Chia Nan Univ Pharm & Sci, Dept Pharm
Natl Cheng Kung Univ Hosp, Dept Internal Med
Natl Cheng Kung Univ Hosp, Ctr Infect Control
Natl Cheng Kung Univ, Dept Med, Med Coll
Natl Cheng Kung Univ, Inst Clin Med, Med Coll
Natl Cheng Kung Univ, Cardiovasc Res Ctr, Med Coll
Chang Gung Univ, Dept Med Lab Sci & Biotechnol
Chang Gung Univ Sci & Technol, Coll Human Ecol, Res Ctr Ind Human Ecol
Chang Gung Univ Sci & Technol, Grad Inst Hlth Ind & Technol, Coll Human Ecol
Chang Gung Univ, Ctr Mol & Clin Immunol
Chang Gung Univ, Res Ctr Bacterial Pathogenesis
Tainan Hosp, Dept Internal Med, Minist Hlth & Welf
Natl Cheng Kung Univ, Ctr Infect Dis & Signaling Res |
| 關鍵字: | Clostridium difficile
inflammasome activation
pyroptosis
ATP-P2X(7) pathway
MyD88 |
| 日期: | 2018-03-16 |
| 上傳時間: | 2019-11-15 15:45:24 (UTC+8) |
| 出版者: | FRONTIERS MEDIA SA |
| 摘要: | Clostridium difficile infection (CDI) is the leading cause of nosocomial infection in hospitalized patients receiving long-term antibiotic treatment. An excessive host inflammatory response is believed to be the major mechanism underlying the pathogenesis of C. difficile infection, and various proinflammatory cytokines such as IL-1 beta are detected in patients with C. difficile infection. IL-1 beta is known to be processed by caspase-1, a cysteine protease that is regulated by a protein complex called the inflammasome, which leads to a specialized form of cell death called pyroptosis. The function of inflammasome activation-induced pyroptosis is to clear or limit the spread of invading pathogens via infiltrated neutrophils. Here, we focused on inflammasome activation induced by intact C. difficile to re-evaluate the nature of inflammasome activation in CDI pathogenesis, which could provide information that leads to an alternative therapeutic strategy for the treatment of this condition in humans. First, we found that caspase-1-dependent IL-1 beta production was induced by C. difficile pathogens in macrophages and increased in a time-dependent manner. Moreover, intracellular toxigenic C. difficile was essential for ATP-P2X(7) pathway of inflammasome activation and subsequent caspase-1-dependent pyroptotic cell death, leading to the loss of membrane integrity and release of intracellular contents such as LDH. Notably, we also observed that bacterial components such as surface layer proteins (SLPs) were released from pyroptotic cells. In addition, pro-IL-1 beta production was completely MyD88 and partially TLR2 dependent. Finally, to investigate the role of the caspase-1-dependent inflammasome in host defense, we found that colonic inflammasome activation was also induced by CDI and that caspase-1 inhibition by Ac-YVAD-CMK led to increased disease progression and C. difficile load. Taken together, the present results suggest that MyD88 and TLR2 are critical component in pro-IL-1 beta production and intracellular C. difficile following the ATP-P2X(7) pathway of inflammasome activation and pyroptosis, which play important roles in host defense through the utilization of inflammation-mediated bacterial clearance mechanisms during C. difficile infection. |
| link: | http://dx.doi.org/10.3389/fcimb.2018.00084 |
| 關聯: | Frontiers in Pharmacology, v.8, 84 |
| 顯示於類別: | [藥學系(所)] 期刊論文
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