The ATP-P2X(7) Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation

doi:10.3389/fcimb.2018.00084

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Title:	The ATP-P2X(7) Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation
Authors:	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
Contributors:	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
Keywords:	Clostridium difficile inflammasome activation pyroptosis ATP-P2X(7) pathway MyD88
Date:	2018-03-16
Issue Date:	2019-11-15 15:45:24 (UTC+8)
Publisher:	FRONTIERS MEDIA SA
Abstract:	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.
???metadata.dc.relation.uri???:	http://dx.doi.org/10.3389/fcimb.2018.00084
Relation:	Frontiers in Pharmacology, v.8, 84
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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