| First Author | Pierini R | Year | 2013 |
| Journal | J Immunol | Volume | 191 |
| Issue | 7 | Pages | 3847-57 |
| PubMed ID | 23975862 | Mgi Jnum | J:205845 |
| Mgi Id | MGI:5546530 | Doi | 10.4049/jimmunol.1203326 |
| Citation | Pierini R, et al. (2013) ASC controls IFN-gamma levels in an IL-18-dependent manner in caspase-1-deficient mice infected with Francisella novicida. J Immunol 191(7):3847-57 |
| abstractText | The inflammasome is a signaling platform that is central to the innate immune responses to bacterial infections. Francisella tularensis is a bacterium replicating within the host cytosol. During F. tularensis subspecies novicida infection, AIM2, an inflammasome receptor sensing cytosolic DNA, activates caspase-1 in an ASC-dependent manner, leading to both pyroptosis and release of the proinflammatory cytokines IL-1beta and IL-18. Activation of this canonical inflammasome pathway is key to limit F. novicida infection. In this study, by comparing the immune responses of AIM2 knockout (KO), ASC(KO), and Casp1(KO) mice in response to F. novicida infection, we observed that IFN-gamma levels in the serum of Casp1(KO) mice were much higher than the levels observed in AIM2(KO) and ASC(KO) mice. This difference in IFN-gamma production was due to a large production of IFN-gamma by NK cells in Casp1(KO) mice that was not observed in ASC(KO) mice. The deficit in IFN-gamma production observed in ASC(KO) mice was not due to a reduced Dock2 expression or to an intrinsic defect of ASC(KO) NK cells. We demonstrate that in infected Casp1(KO) mice, IFN-gamma production is due to an ASC-dependent caspase-1-independent pathway generating IL-18. Furthermore, we present in vitro data suggesting that the recently described AIM2/ASC/caspase-8 noncanonical pathway is responsible for the caspase-1-independent IL-18 releasing activity. To our knowledge, this study is the first in vivo evidence of an alternative pathway able to generate in a caspase-1-independent pathway bioactive IL-18 to boost the production of IFN-gamma, a cytokine critical for the host antibacterial response. |
