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The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
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Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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Hemolysis-induced lethality involves inflammasome activation by heme.

Fabianno F Dutra1, Letícia S Alves1, Danielle Rodrigues1

  • 1Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, Brazil;

Proceedings of the National Academy of Sciences of the United States of America
|September 17, 2014
PubMed
Summary

Extracellular heme activates macrophages via the NLRP3 inflammasome pathway, independent of cell damage. This finding reveals key mechanisms in heme-induced inflammation and potential therapeutic targets for diseases involving hemolysis.

Keywords:
NOX2ROSSykinflammationmitochondria

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Area of Science:

  • Immunology
  • Cellular Biology
  • Pathophysiology

Background:

  • Extracellular heme, a byproduct of red blood cell breakdown, possesses prooxidant and inflammatory properties.
  • Heme contributes to the pathology of diseases such as malaria, sepsis, and sickle cell disease.
  • The precise mechanisms by which innate immune cells detect heme remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which heme is sensed by innate immune cells.
  • To identify the specific inflammasome pathway activated by heme in macrophages.
  • To investigate the role of heme-induced immune activation in disease pathogenesis.

Main Methods:

  • Utilized LPS-primed macrophages to study heme-induced activation.
  • Investigated the involvement of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome.
  • Assessed the requirement for spleen tyrosine kinase, NADPH oxidase-2, mitochondrial reactive oxygen species, and potassium efflux.
  • Examined the independence from heme internalization, lysosomal damage, ATP release, P2X7 receptor, and cell death.

Main Results:

  • Heme, but not iron-free porphyrins, activated LPS-primed macrophages.
  • Heme-induced activation of the NLRP3 inflammasome and subsequent IL-1β processing were identified.
  • Key signaling molecules including spleen tyrosine kinase, NADPH oxidase-2, mitochondrial ROS, and K+ efflux were essential for NLRP3 activation by heme.
  • Heme internalization, lysosomal damage, P2X7, and cell death were not required for NLRP3 activation.

Conclusions:

  • Macrophages sense extracellular heme through a pathway involving spleen tyrosine kinase, NADPH oxidase-2, mitochondrial ROS, and K+ efflux, leading to NLRP3 inflammasome activation.
  • This heme-sensing mechanism is critical for IL-1β processing and contributes to lethality in sterile hemolysis.
  • Understanding these pathways offers potential therapeutic targets for heme-related inflammatory diseases.