| Autor: |
Dutra FF; Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil;, Alves LS; Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil;, Rodrigues D; Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil;, Fernandez PL; Centro de Biología Celular y Molecular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología, 0843-01103, Panama City, Panama;, de Oliveira RB; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; and., Golenbock DT; Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; and., Zamboni DS; Departamento de Biologia Celular, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, 14049-900, São Paulo, Brazil., Bozza MT; Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil; mbozza@micro.ufrj.br. |
| Abstrakt: |
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-1β 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. |
