Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria

Strangward, Patrick, Haley, Michael, Garcia-Ambornoz, M, Brrington, Jack, Shaw, Tovah, Dookle, Rebecca, Zeef, Leo, Baker, Syed, Winter, Emma, Tzeng, Te-Chen, Golenbock, Douglas, Crulckshank, Sheena, Allen, Stuart, Craig, Alister ORCID: https://orcid.org/0000-0003-0914-6164, Llew, Foo, Brough, David and Couper, Kevin (2018) 'Targeting the IL33-NLRP3 axis improves therapy for experimental cerebral malaria'. Proceedings of the National Academy of Sciences.

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Abstract

Cerebral 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 IL1β 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 IL1β 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

Item Type:	Article
Subjects:	QU Biochemistry > Biochemistry of the Human Body > QU 107 Growth substances QW Microbiology and Immunology > Immunity by Type > QW 568 Cellular immunity. Immunologic cytotoxicity. Immunocompetence. Immunologic factors (General) WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):	https://doi.org/10.1073/pnas.1801737115
Depositing User:	Stacy Murtagh
Date Deposited:	13 Jun 2018 14:23
Last Modified:	17 Jul 2019 14:15
URI:	https://archive.lstmed.ac.uk/id/eprint/8772

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