Hemolysis-induced lethality involves inflammasome activation by heme

被引:264
作者
Dutra, Fabianno F. [1 ]
Alves, Leticia S. [1 ]
Rodrigues, Danielle [1 ]
Fernandez, Patricia L. [2 ]
de Oliveira, Rosane B. [3 ]
Golenbock, Douglas T. [3 ]
Zamboni, Dario S. [4 ]
Bozza, Marcelo T. [1 ]
机构
[1] Univ Fed Rio de Janeiro, Inst Microbiol, Dept Imunol, Lab Inflamacao & Imunidade, BR-21941902 Rio De Janeiro, Brazil
[2] Inst Invest Cient Serv Alta Tecnol, Ctr Biol Celular & Mol Enfermedades, Panama City 084301103, Panama
[3] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA
[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular, BR-14049900 Sao Paulo, Brazil
关键词
inflammation; mitochondria; ROS; NOX2; Syk; NLRP3; INFLAMMASOME; NALP3; NEUTROPHIL MIGRATION; OXIDATIVE STRESS; CELL ACTIVATION; NADPH OXIDASE; OXYGENASE; MICE; IRON; EXPRESSION;
D O I
10.1073/pnas.1405023111
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-1 beta 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.
引用
收藏
页码:E4110 / E4118
页数:9
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