Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS.
Retrovirology
; 11: 35, 2014 May 13.
Article
em En
| MEDLINE
| ID: mdl-24886384
ABSTRACT
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-1ß 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-1ß, 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-1ß in human microglia at 4 hr post-infection with peak IL-1ß release at 24 hr, which was accompanied by intracellular ASC translocation and caspase-1 activation. HIV-dependent release of IL-1ß 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-1ß production and similarly, HIV-1 envelope pseudotyped viral particles induced IL-1ß 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-1ß. 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-1ß, 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Encefalopatias
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Infecções por HIV
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Síndrome da Imunodeficiência Adquirida
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HIV-1
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Microglia
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Inflamassomos
Limite:
Animals
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Female
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Humans
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Pregnancy
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article