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: Tobias Hoegen, Nadin Tremel, Matthias Klein, Barbara Angele, Hermann Wagner, Carsten Kirschning, Hans-Walter Pfister, Adriano Fontana, Sven Hammerschmidt, Uwe Koedel
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 187 Issue 10 Pg. 5440-51 (Nov 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 22003197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytoskeletal Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nlrp3 protein, mouse
• Pycard protein, mouse
• Adenosine Triphosphate
• Cathepsin B
• Ctsb protein, mouse

Topics

• Adenosine Triphosphate (physiology)
• Animals
• Apoptosis Regulatory Proteins
• Brain Injuries (enzymology, immunology, pathology)
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics, metabolism, physiology)
• Cathepsin B (metabolism)
• Cell Line, Tumor
• Cytoskeletal Proteins (deficiency, genetics)
• Disease Models, Animal
• Humans
• Hydrogen-Ion Concentration
• Lysosomes (enzymology, immunology, metabolism)
• Meningitis, Pneumococcal (enzymology, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Severity of Illness Index