| The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release. | |
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MedLine Citation:
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PMID: 22003197 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Tobias Hoegen; Nadin Tremel; Matthias Klein; Barbara Angele; Hermann Wagner; Carsten Kirschning; Hans-Walter Pfister; Adriano Fontana; Sven Hammerschmidt; Uwe Koedel |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-14 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: - ISSN: 1550-6606 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-17 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Neurology, Clinic of the University of Munich, D-81377 Munich, Germany; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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