Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria.
Glia
; 61(3): 441-52, 2013 Mar.
Article
em En
| MEDLINE
| ID: mdl-23280493
ABSTRACT
The inflammasome is a multimolecular complex that orchestrates the activation of proinflammatory caspases and interleukin (IL)-1ß, which is generally increased in the cerebrospinal fluids of patients with tuberculous meningitis. However, it has not been clarified whether mycobacteria can activate the inflammasome and induce IL-1ß maturation in microglia. In this study, we found that the priming of primary murine microglial cells with conditioned media from cultures of macrophages infected with Mycobacterium tuberculosis (Mtb) led to robust activation of caspase-1 and IL-1ß secretion after Mtb stimulation. Potassium efflux and the lysosomal proteases cathepsin B and cathepsin L were required for the Mtb-induced caspase-1 activation and maturation of IL-1ß production in primed microglia. Mtb-induced IL-1ß maturation was also found to depend on the nucleotide binding and oligomerization of domain-like receptor family pyrin domain containing 3 protein (NLRP3) and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), as well as the generation of mitochondrial reactive oxygen species (ROS). Notably, the priming of microglia with tumor necrosis factor-α or oncostatin M resulted in caspase-1 cleavage and IL-1ß secretion in response to Mtb. Moreover, dexamethasone, as an adjunctive therapy for patients of tuberculous meningitis, significantly reduced the Mtb-induced maturation of IL-1ß through inhibition of mitochondrial ROS generation. Collectively, these data suggest that Mtb stimulation induces activation of the microglial NLRP3 inflammasome (composed of NLRP3, ASC, and cysteine protease caspase-1) through microglia-leukocyte interactions as a priming signal, and that dexamethasone decreases inflammasome activation through inhibition of ROS of mitochondrial origin.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
/
Microglia
/
Inflamassomos
/
Macrófagos
Limite:
Animals
Idioma:
En
Revista:
Glia
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Coréia do Sul