| First Author | Mitchell AJ | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 10 | Pages | 4970-80 |
| PubMed ID | 23071286 | Mgi Jnum | J:190696 |
| Mgi Id | MGI:5449480 | Doi | 10.4049/jimmunol.1201687 |
| Citation | Mitchell AJ, et al. (2012) Inflammasome-dependent IFN-gamma drives pathogenesis in Streptococcus pneumoniae meningitis. J Immunol 189(10):4970-80 |
| abstractText | The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-gamma) was strongly induced, and IFN-gamma(-/-) mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-gamma. Furthermore, production of IFN-gamma was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-gamma induction. The influence of IFN-gamma gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-gamma(-/-) mice, both monocyte recruitment and CCL2 production were less in infected IFN-gamma(-/-) mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-gamma(-/-) mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-gamma(-/-) mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-gamma contributes via multiple pathways to pathology during S. pneumoniae meningitis. |
