Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS

Retrovirology

Christopher Power¹  David I Broadhurst¹  William G Branton¹  Ferdinand Maingat¹  Brienne A McKenzie¹  Manmeet K Mamik¹  Stacey N Reinke¹  John G Walsh¹ 

[1] Department of Medicine (Neurology), Heritage Medical Research Centre 6–11, University of Alberta, Edmonton T6G 2S2, Canada

关键词: Nervous system;    ASC microglia;    Caspase-1;    FIV;    HIV-1;    IL-1beta;    NLRP3;    Inflammmasome;   

Others  :  801939
DOI  :  10.1186/1742-4690-11-35

 received in 2013-11-20, accepted in 2014-04-24,  发布年份 2014

【 摘 要 】

Background

Human immunodeficiency virus type 1(HIV-1) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with accompanying neurological deficits. Induction of inflammasomes causes cleavage and release of IL-1β and IL-18, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV-associated brain disease is unknown.

Results

Investigation of inflammasome-associated genes revealed that IL-1β, IL-18 and caspase-1 were induced in brains of HIV-infected persons and detected in brain microglial cells. HIV-1 infection induced pro-IL-1β in human microglia at 4 hr post-infection with peak IL-1β release at 24 hr, which was accompanied by intracellular ASC translocation and caspase-1 activation. HIV-dependent release of IL-1β from a human macrophage cell line, THP-1, was inhibited by NLRP3 deficiency and high extracellular [K⁺]. Exposure of microglia to HIV-1 gp120 caused IL-1β production and similarly, HIV-1 envelope pseudotyped viral particles induced IL-1β release, unlike VSV-G pseudotyped particles. Infection of cultured feline macrophages by the related lentivirus, feline immunodeficiency virus (FIV), also resulted in the prompt induction of IL-1β. In vivo FIV infection activated multiple inflammasome-associated genes in microglia, which was accompanied by neuronal loss in cerebral cortex and neurological deficits. Multivariate analyses of data from FIV-infected and uninfected animals disclosed that IL-1β, NLRP3 and caspase-1 expression in cerebral cortex represented key molecular determinants of neurological deficits.

Conclusions

NLRP3 inflammasome activation was an early and integral aspect of lentivirus infection of microglia, which was associated with lentivirus-induced brain disease. Inflammasome activation in the brain might represent a potential target for therapeutic interventions in HIV/AIDS.

【 授权许可】

   
2014 Walsh et al.; licensee BioMed Central Ltd.

【 图 表 】

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