| First Author | Labbé K | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 9 | Pages | 5495-502 |
| PubMed ID | 20876354 | Mgi Jnum | J:165191 |
| Mgi Id | MGI:4836428 | Doi | 10.4049/jimmunol.1002517 |
| Citation | Labbe K, et al. (2010) Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling. J Immunol 185(9):5495-502 |
| abstractText | Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-kappaB and is associated with susceptibility to bacterial sepsis. A single-nucleotide polymorphism (T(125)C) in human Casp12 restricts its expression to Africa, Southeast Asia, and South America. Here, we investigated the role of caspase-12 in the control of parasite replication and pathogenesis in malaria and report that caspase-12 dampened parasite clearance in blood-stage malaria and modulated susceptibility to cerebral malaria. This response was independent of the caspase-1 inflammasome, as casp1(-/-) mice were indistinguishable from wild-type animals in response to malaria, but dependent on enhanced NF-kappaB activation. Mechanistically, caspase-12 competed with NEMO for association with IkappaB kinase-alpha/beta, effectively preventing the formation of the IkappaB kinase complex and inhibiting downstream transcriptional activation by NF-kappaB. Systemic inhibition of NF-kappaB or Ab neutralization of IFN-gamma reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection. |
