Heme Drives Hemolysis-Induced Susceptibility to Infection via Disruption of Phagocyte Functions

Nat Immunol. 2016 Dec;17(12):1361-1372. doi: 10.1038/ni.3590. Epub 2016 Oct 31.

Abstract

Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8. A chemical screening approach revealed that quinine effectively prevented heme effects on the cytoskeleton, restored phagocytosis and improved survival in sepsis. These mechanistic insights provide potential therapeutic targets for patients with sepsis or hemolytic disorders.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use
  • Cytoskeleton / metabolism
  • Female
  • Gram-Negative Bacterial Infections / drug therapy
  • Gram-Negative Bacterial Infections / immunology*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Heme / metabolism*
  • Heme Oxygenase-1 / genetics
  • Hemolysis / drug effects
  • Hemolysis / immunology*
  • Humans
  • Immune Evasion
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis* / drug effects
  • Quinine / therapeutic use
  • RAW 264.7 Cells
  • Sepsis / drug therapy
  • Sepsis / immunology*
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • Anti-Bacterial Agents
  • Dock8 protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Membrane Proteins
  • Heme
  • Quinine
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • cdc42 GTP-Binding Protein