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.

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

“…We found that IFN-g production in the brain following S. pneumoniae inoculation was dependent upon ASC, which is a key adaptor molecule for multiple inflammasomes. Our data are consistent with reports that argue that the pneumococcal toxin pneumolysin is recognized via ASC-dependent inflammasomes, in particular those containing NLRP3 and/or AIM2 (16)(17)(18)(19). Recently, IFN-g production secondary to inflammasome-mediated IL-18 activation was reported in response to flagellated bacteria (77) or to S. pneumoniae during lung infection (18).…”

“…However, the clear dependence of IFN-g upon ASC and IL-18 shown in this study indicates that IL-18 production secondary to inflammasome formation is the dominant pathway of IFN-g production during pneumococcal infection in the brain. This is of particular relevance, because a recent study showed that the NLRP3 inflammasome contributes to pathology in pneumococcal meningitis through production of IL-1b and IL-18, and this was associated with diminished leukocyte recruitment in NLRP3-deficient animals (17). Our data extend these findings to show that inflammasome-dependent pathology is, at least in large part, dependent upon IL-18-mediated induction of IFN-g rather than through direct effects of IL-1b and IL-18.…”

“…The presence of S. pneumoniae is initially sensed by resident cells via interaction of microbial products with pattern recognition receptors, including TLR2 and TLR4 (12)(13)(14), as well as NOD2 (15). More recently, it was shown that S. pneumoniae may also be recognized by inflammasomes that are dependent upon the adaptor molecule ASC (16)(17)(18)(19). Together, these pathways initiate immune activation and lead to production of inflammatory cytokines and chemokines that subsequently mediate the recruitment of leukocytes to the site of infection (20)(21)(22)(23)(24)(25)(26).…”

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Accumulating evidence indicates that NLRP3 inflammasomes play a significant role in the recognition of and response to bacterial infection. Although there is no direct evidence for the interaction of bacterial ligands with NLRP3, a variety of pathogenic bacteria including Staphylococcus aureus (Craven et al 2009;Holzinger et al 2012;Kebaier et al 2012;Maher et al 2013;McGilligan et al 2013;Muñoz-Planillo et al 2009), Streptococcus pneumoniae (Hoegen et al 2011;McNeela et al 2010;Witzenrath et al 2011) and Listeria monocytogenes (Meixenberger et al 2010) have been Arch. Immunol.…”

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…1 Caspase-1 activation and interleukin-1 (IL-1) release have a central role in many disorders with an inflammatory component, 2 which comprises different diseases of the central nervous system (CNS) such as multiple sclerosis, Alzheimer disease, meningitis, or stroke. [3][4][5][6][7][8] The potential molecular signals, which activate the inflammasomes in the CNS, have already been delineated in detail before. 8,9 Thus, this overview aims at a more global, system biologic view of the potential role of the inflammasomes in CNS diseases and accounts for recent discoveries in related research fields.…”