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

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Abstract

© 2014 Chigaev et al.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, αβ-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 Gα-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.

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Chigaev, A., Smagley, Y., & Sklar, L. A. (2014). Carbon monoxide down-regulates α4β1 integrin-specific ligand binding and cell adhesion: A possible mechanism for cell mobilization. BMC Immunology, 15(1). https://doi.org/10.1186/s12865-014-0052-1

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