title: The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release.
abstract: Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18-binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.
authors: Department of Neurology, Clinic of the University of Munich, D-81377 Munich, Germany.
authors: Tobias
authors: T
authors: Hoegen
authors: Nadin
authors: N
authors: Tremel
authors: Matthias
authors: M
authors: Klein
authors: Barbara
authors: B
authors: Angele
authors: Hermann
authors: H
authors: Wagner
authors: Carsten
authors: C
authors: Kirschning
authors: Hans-Walter
authors: HW
authors: Pfister
authors: Adriano
authors: A
authors: Fontana
authors: Sven
authors: S
authors: Hammerschmidt
authors: Uwe
authors: U
authors: Koedel
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001930:Brain Injuries / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002401:Cathepsin B / Q000378:metabolism*; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D008586:Meningitis, Pneumococcal / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012720:Severity of Illness Index
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D000255:Adenosine Triphosphate; D002401:Cathepsin B; C533915:Ctsb protein, mouse