Caspase-12 dampens the immune response to malaria independently of the inflammasome by targeting NF-kappaB signaling.
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.
Labbé
Katherine
K
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Miu
Jenny
J
Yeretssian
Garabet
G
Serghides
Lena
L
Tam
Mifong
M
Finney
Constance A
CA
Erdman
Laura K
LK
Goulet
Marie-Line
ML
Kain
Kevin C
KC
Stevenson
Mary M
MM
Saleh
Maya
M
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*
D016207:Cytokines; D016328:NF-kappa B; C506440:Casp12 protein, mouse; D053454:Caspase 12