Hemolysis-induced lethality involves inflammasome activation by heme.
Proc Natl Acad Sci U S A
; 111(39): E4110-8, 2014 Sep 30.
Article
em En
| MEDLINE
| ID: mdl-25225402
ABSTRACT
The increase of extracellular heme is a hallmark of hemolysis or extensive cell damage. Heme has prooxidant, cytotoxic, and inflammatory effects, playing a central role in the pathogenesis of malaria, sepsis, and sickle cell disease. However, the mechanisms by which heme is sensed by innate immune cells contributing to these diseases are not fully characterized. We found that heme, but not porphyrins without iron, activated LPS-primed macrophages promoting the processing of IL-1ß dependent on nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3). The activation of NLRP3 by heme required spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and K(+) efflux, whereas it was independent of heme internalization, lysosomal damage, ATP release, the purinergic receptor P2X7, and cell death. Importantly, our results indicated the participation of macrophages, NLRP3 inflammasome components, and IL-1R in the lethality caused by sterile hemolysis. Thus, understanding the molecular pathways affected by heme in innate immune cells might prove useful to identify new therapeutic targets for diseases that have heme release.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inflamassomos
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Heme
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Hemólise
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article