title: Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling.
abstract: Pathogen sensing by the inflammasome activates inflammatory caspases that mediate inflammation and cell death. Caspase-12 antagonizes the inflammasome and NF-κB 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-κB activation. Mechanistically, caspase-12 competed with NEMO for association with IκB kinase-α/β, effectively preventing the formation of the IκB kinase complex and inhibiting downstream transcriptional activation by NF-κB. Systemic inhibition of NF-κB or Ab neutralization of IFN-γ reversed the increased resistance of casp12(-/-) mice to blood-stage malaria infection.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
authors.forename: Katherine
authors.initials: K
authors.lastname: Labbé
authors.forename: Jenny
authors.initials: J
authors.lastname: Miu
authors.forename: Garabet
authors.initials: G
authors.lastname: Yeretssian
authors.forename: Lena
authors.initials: L
authors.lastname: Serghides
authors.forename: Mifong
authors.initials: M
authors.lastname: Tam
authors.forename: Constance A
authors.initials: CA
authors.lastname: Finney
authors.forename: Laura K
authors.initials: LK
authors.lastname: Erdman
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Goulet
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.forename: Mary M
authors.initials: MM
authors.lastname: Stevenson
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
mesh_terms: D000818:Animals; D053454:Caspase 12 / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D008288:Malaria / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C506440:Casp12 protein, mouse; D053454:Caspase 12