The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release

• Published in: The Journal of immunology (1950) Vol. 187; no. 10; pp. 5440 - 5451
• Main Authors: Hoegen, Tobias, Tremel, Nadin, Klein, Matthias, Angele, Barbara, Wagner, Hermann, Kirschning, Carsten, Pfister, Hans-Walter, Fontana, Adriano, Hammerschmidt, Sven, Koedel, Uwe
• Format: Journal Article
• Language: English
• Published: United States 15-11-2011
• Subjects: Adenosine Triphosphate - physiology; Animals; Apoptosis Regulatory Proteins; Brain Injuries - enzymology; Brain Injuries - immunology; Brain Injuries - pathology; CARD Signaling Adaptor Proteins; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - physiology; Cathepsin B - secretion; Cell Line, Tumor; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Disease Models, Animal; Humans; Hydrogen-Ion Concentration; Lysosomes - enzymology; Lysosomes - immunology; Lysosomes - secretion; Meningitis, Pneumococcal - enzymology; Meningitis, Pneumococcal - immunology; Meningitis, Pneumococcal - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; NLR Family, Pyrin Domain-Containing 3 Protein; Severity of Illness Index; Streptococcus pneumoniae
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100790

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.