title: Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia.
abstract: Streptococcus pneumoniae is responsible for significant mortality and morbidity worldwide and causes invasive pneumococcal diseases including pneumococcal meningitis. Pyroptosis is caspase-1-dependent inflammatory cell death and is known to be induced by various microbial infections. In the present study, we investigated the molecular mechanisms that regulate pyroptosis induced by S. pneumoniae in microglia. Our results revealed that S. pneumoniae induced pyroptosis through caspase-1 activation and IL-1β production. We also found that the activation of caspase-1 and the maturation of IL-1β and IL-18 in the S. pneumoniae-triggered pyroptotic cell death process were mediated by NLRP3 inflammasome. In addition, pneumococcal infection increased the expression of autophagy-related genes and induced autophagosome formation. We also showed that the inhibition of autophagy promoted pneumococcus-induced pyroptosis. Furthermore, ROS was generated by pneumococcal infection and inhibited caspase-1 activation within 4 h of infection. However, in the late phase of infection, IL-1β secretion and caspase-1-dependent cell death were induced by ROS. These results suggest that autophagy induction transiently delay pyroptosis induced by S. pneumoniae in microglia. Our study also revealed that the activation of caspase-1 and the production of IL-1β were induced by pneumolysin and that pneumolysin triggered pyroptosis in microglial cells. Similar to the in vitro results, S. pneumoniae induced caspase-1 activation and caspase-1-dependent cytokine maturation in the mouse meningitis model. Thus, the present data demonstrate that S. pneumoniae induces pyroptosis in murine microglia and that NLRP3 inflammasome is critical for caspase-1 activation during the process. Furthermore, the induction of autophagy could transiently protect microglia from pyroptosis.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, Republic of Korea.
authors.forename: Ji-Yun
authors.initials: JY
authors.lastname: Kim
authors.affiliation: School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia.
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.|Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, Republic of Korea.
authors.forename: Dong-Kwon
authors.initials: DK
authors.lastname: Rhee
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Kyunggi-do, Republic of Korea.
authors.forename: Suhkneung
authors.initials: S
authors.lastname: Pyo
mesh_terms: D000818:Animals; D001343:Autophagy; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D054884:Host-Pathogen Interactions; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D008586:Meningitis, Pneumococcal / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000069292:Pyroptosis; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000276:immunology / Q000472:pathogenicity*; D013997:Time Factors; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C587672:IL1B protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D020170:Caspase 1
keywords: S. pneumoniae; autophagy; microglia; pneumolysin; pyroptosis