Carbon monoxide down-regulates α4β1 integrin-specific ligand binding and cell adhesion: a possible mechanism for cell mobilization

BMC Immunol. 2014 Oct 31;15:52. doi: 10.1186/s12865-014-0052-1.


Background: Carbon monoxide (CO), a byproduct of heme degradation, is attracting growing attention from the scientific community. At physiological concentrations, CO plays a role as a signal messenger that regulates a number of physiological processes. CO releasing molecules are under evaluation in preclinical models for the management of inflammation, sepsis, ischemia/reperfusion injury, and organ transplantation. Because of our discovery that nitric oxide signaling actively down-regulates integrin affinity and cell adhesion, and the similarity between nitric oxide and CO-dependent signaling, we studied the effects of CO on integrin signaling and cell adhesion.

Results: We used a cell permeable CO releasing molecule (CORM-2) to elevate intracellular CO, and a fluorescent Very Late Antigen-4 (VLA-4, α4β1-integrin)-specific ligand to evaluate the integrin state in real-time on live cells. We show that the binding of the ligand can be rapidly down-modulated in resting cells and after inside-out activation through several Gαi-coupled receptors. Moreover, cell treatment with hemin, a natural source of CO, resulted in comparable VLA-4 ligand dissociation. Inhibition of VLA-4 ligand binding by CO had a dramatic effect on cell-cell interaction in a VLA-4/VCAM-1-dependent cell adhesion system.

Conclusions: We conclude that the CO signaling pathway can rapidly down-modulate binding of the VLA-4 -specific ligand. We propose that CO-regulated integrin deactivation provides a basis for modulation of immune cell adhesion as well as rapid cell mobilization, for example as shown for splenic monocytes in response to surgically induced ischemia of the myocardium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Monoxide / pharmacology*
  • Cell Adhesion / drug effects
  • Cell Membrane Permeability / drug effects
  • Cyclic GMP / metabolism
  • Down-Regulation / drug effects*
  • Guanylate Cyclase / metabolism
  • Heme Oxygenase (Decyclizing) / metabolism
  • Hemin / pharmacology
  • Humans
  • Integrin alpha4beta1 / metabolism*
  • Ligands
  • Mice
  • Oligopeptides / metabolism
  • Phenylurea Compounds / metabolism
  • Protein Subunits / metabolism
  • Receptors, CXCR4 / metabolism
  • Receptors, Interleukin-8B / metabolism
  • Signal Transduction / drug effects
  • Solubility
  • Substrate Specificity / drug effects
  • Transfection
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • 4-((N'-2-methylphenyl)ureido)phenylalanyl-leucyl-alpha-aspartyl-valyl-prolyl-alanyl-alanyl-lysine
  • Integrin alpha4beta1
  • Ligands
  • Oligopeptides
  • Phenylurea Compounds
  • Protein Subunits
  • Receptors, CXCR4
  • Receptors, Interleukin-8B
  • Vascular Cell Adhesion Molecule-1
  • Hemin
  • Carbon Monoxide
  • Heme Oxygenase (Decyclizing)
  • Guanylate Cyclase
  • Cyclic GMP