The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation
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 proin...
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Frontiers Media S.A.
2018-03-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fcimb.2018.00084/full |
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record_format |
Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ya-Hui Liu Ya-Hui Liu Yung-Chi Chang Liang-Kuei Chen Po-An Su Po-An Su Wen-Chien Ko Wen-Chien Ko Wen-Chien Ko Yau-Sheng Tsai Yau-Sheng Tsai Yi-Hsuan Chen Hsin-Chih Lai Hsin-Chih Lai Hsin-Chih Lai Cheng-Yeu Wu Cheng-Yeu Wu Yuan-Pin Hung Pei-Jane Tsai Pei-Jane Tsai Pei-Jane Tsai |
spellingShingle |
Ya-Hui Liu Ya-Hui Liu Yung-Chi Chang Liang-Kuei Chen Po-An Su Po-An Su Wen-Chien Ko Wen-Chien Ko Wen-Chien Ko Yau-Sheng Tsai Yau-Sheng Tsai Yi-Hsuan Chen Hsin-Chih Lai Hsin-Chih Lai Hsin-Chih Lai Cheng-Yeu Wu Cheng-Yeu Wu Yuan-Pin Hung Pei-Jane Tsai Pei-Jane Tsai Pei-Jane Tsai The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation Frontiers in Cellular and Infection Microbiology Clostridium difficile inflammasome activation pyroptosis ATP-P2X7 pathway MyD88 |
author_facet |
Ya-Hui Liu Ya-Hui Liu Yung-Chi Chang Liang-Kuei Chen Po-An Su Po-An Su Wen-Chien Ko Wen-Chien Ko Wen-Chien Ko Yau-Sheng Tsai Yau-Sheng Tsai Yi-Hsuan Chen Hsin-Chih Lai Hsin-Chih Lai Hsin-Chih Lai Cheng-Yeu Wu Cheng-Yeu Wu Yuan-Pin Hung Pei-Jane Tsai Pei-Jane Tsai Pei-Jane Tsai |
author_sort |
Ya-Hui Liu |
title |
The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
title_short |
The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
title_full |
The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
title_fullStr |
The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
title_full_unstemmed |
The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation |
title_sort |
atp-p2x7 signaling axis is an essential sentinel for intracellular clostridium difficile pathogen-induced inflammasome activation |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular and Infection Microbiology |
issn |
2235-2988 |
publishDate |
2018-03-01 |
description |
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-1β are detected in patients with C. difficile infection. IL-1β 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-1β 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-P2X7 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-1β 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-1β production and intracellular C. difficile following the ATP-P2X7 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. |
topic |
Clostridium difficile inflammasome activation pyroptosis ATP-P2X7 pathway MyD88 |
url |
https://www.frontiersin.org/article/10.3389/fcimb.2018.00084/full |
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doaj-50db14e5e6fa4616970d4a75c445dbef2020-11-24T22:17:52ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-03-01810.3389/fcimb.2018.00084324485The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome ActivationYa-Hui Liu0Ya-Hui Liu1Yung-Chi Chang2Liang-Kuei Chen3Po-An Su4Po-An Su5Wen-Chien Ko6Wen-Chien Ko7Wen-Chien Ko8Yau-Sheng Tsai9Yau-Sheng Tsai10Yi-Hsuan Chen11Hsin-Chih Lai12Hsin-Chih Lai13Hsin-Chih Lai14Cheng-Yeu Wu15Cheng-Yeu Wu16Yuan-Pin Hung17Pei-Jane Tsai18Pei-Jane Tsai19Pei-Jane Tsai20Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Pathology, National Cheng Kung University Hospital, Tainan, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, TaiwanDivision of Infectious Diseases, Chi Mei Medical Center, Tainan, TaiwanDepartment of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, TaiwanDepartment of Internal Medicine, National Cheng Kung University Hospital, Tainan, TaiwanCenter for Infection Control, National Cheng Kung University Hospital, Tainan, TaiwanDepartment of Medicine, College of Medicine, National Cheng Kung University, Tainan, TaiwanInstitute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, TaiwanCardiovascular Research Center, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan0Department of Medical Laboratory Science and Biotechnology, Chang Gung University, Taoyaun, Taiwan1Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyaun, Taiwan2Graduate Institute of Health Industry and Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyaun, Taiwan3Center for Molecular and Clinical Immunology, Chang Gung University, Taoyaun, Taiwan4Research Center of Bacterial Pathogenesis, Chang Gung University, Taoyaun, Taiwan5Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, TaiwanDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, TaiwanDepartment of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan6Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, TaiwanClostridium 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-1β are detected in patients with C. difficile infection. IL-1β 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-1β 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-P2X7 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-1β 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-1β production and intracellular C. difficile following the ATP-P2X7 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.https://www.frontiersin.org/article/10.3389/fcimb.2018.00084/fullClostridium difficileinflammasome activationpyroptosisATP-P2X7 pathwayMyD88 |