Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria
Haley, Michael J.
Albornoz, Manuel G.
Baker, Syed M.
Golenbock, Douglas T.
Cruickshank, Sheena M.
Allan, Stuart M.
Couper, Kevin N.
UMass Chan AffiliationsDepartment of Medicine, Division of Infectious Diseases and Immunology
Document TypeJournal Article
Immunology and Infectious Disease
MetadataShow full item record
AbstractCerebral malaria (CM) is a serious neurological complication caused by Plasmodium falciparum infection. Currently, the only treatment for CM is the provision of antimalarial drugs; however, such treatment by itself often fails to prevent death or development of neurological sequelae. To identify potential improved treatments for CM, we performed a nonbiased whole-brain transcriptomic time-course analysis of antimalarial drug chemotherapy of murine experimental CM (ECM). Bioinformatics analyses revealed IL33 as a critical regulator of neuroinflammation and cerebral pathology that is down-regulated in the brain during fatal ECM and in the acute period following treatment of ECM. Consistent with this, administration of IL33 alongside antimalarial drugs significantly improved the treatment success of established ECM. Mechanistically, IL33 treatment reduced inflammasome activation and IL1beta production in microglia and intracerebral monocytes in the acute recovery period following treatment of ECM. Moreover, treatment with the NLRP3-inflammasome inhibitor MCC950 alongside antimalarial drugs phenocopied the protective effect of IL33 therapy in improving the recovery from established ECM. We further showed that IL1beta release from macrophages was stimulated by hemozoin and antimalarial drugs and that this was inhibited by MCC950. Our results therefore demonstrate that manipulation of the IL33-NLRP3 axis may be an effective therapy to suppress neuroinflammation and improve the efficacy of antimalarial drug treatment of CM.
Strangward P, Haley MJ, Albornoz MG, Barrington J, Shaw T, Dookie R, Zeef L, Baker SM, Winter E, Tzeng TC, Golenbock DT, Cruickshank SM, Allan SM, Craig A, Liew FY, Brough D, Couper KN. Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria. Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):7404-7409. doi: 10.1073/pnas.1801737115. Epub 2018 Jun 28. PMID: 29954866; PMCID: PMC6048513. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/35200
Full list of authors omitted for brevity. For full list see article.