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

Chigaev A, Smagley Y, Sklar LA - BMC Immunol. (2014)

Bottom Line: Moreover, cell treatment with hemin, a natural source of CO, resulted in comparable VLA-4 ligand dissociation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and University of New Mexico Cancer Center, Albuquerque 87131, NM, USA. achigaev@salud.unm.edu.

ABSTRACT

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.

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CO signaling cascade and small molecules used to modulate this pathway. Endogenous carbon monoxide is generated by heme oxygenase (HO). In cells CO reacts with hemeproteins. One of the CO receptors is the guanylyl cyclase (GC) that produces the intracellular messenger cyclic GMP (cGMP). cGMP interacts with the cGMP-dependent protein kinase (PKG), which phosphorylates multiple substrates, and participates in signal propagation. The carbon monoxide donor provides an exogenous source of CO. The natural HO substrate hemin increases CO production because conversion of heme into biliverdin represents the rate-limiting step in heme degradation [5]. The activator of soluble guanylyl cyclase binds to GC, and induces enzyme activation in the absence of CO. The cell permeable analog of cGMP diffuses across the plasma membrane, and thus, activates cGMP-dependent signaling.
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Fig1: CO signaling cascade and small molecules used to modulate this pathway. Endogenous carbon monoxide is generated by heme oxygenase (HO). In cells CO reacts with hemeproteins. One of the CO receptors is the guanylyl cyclase (GC) that produces the intracellular messenger cyclic GMP (cGMP). cGMP interacts with the cGMP-dependent protein kinase (PKG), which phosphorylates multiple substrates, and participates in signal propagation. The carbon monoxide donor provides an exogenous source of CO. The natural HO substrate hemin increases CO production because conversion of heme into biliverdin represents the rate-limiting step in heme degradation [5]. The activator of soluble guanylyl cyclase binds to GC, and induces enzyme activation in the absence of CO. The cell permeable analog of cGMP diffuses across the plasma membrane, and thus, activates cGMP-dependent signaling.

Mentions: Endogenous CO is produced inside cells as a product of enzymatic degradation of heme catalyzed by the enzyme heme oxygenase (HO) that consists of two isoforms: HO-1 is inducible, and HO-2 is a constitutive form [20]. HO is localized in the cytosol and mitochondria [21]. The major source of heme for CO production is hemoglobin, and other hemeproteins (Figure 1). CO has been shown to stimulate soluble guanylyl cyclase, stimulate vasodilatation, block cell proliferation, participate in neural transmission, and inhibit platelet aggregation (see [20] and references therein). CO targets several heme-containing proteins and soluble guanylyl cyclase (sGC) was recognized as the first and the most studied “CO receptor”. Multiple physiological effects including vasodilatation and platelet aggregation are attributed to the cGMP/PKG-dependent arm of the CO signaling pathway. Other signaling molecules such as p38 MAPK, ERK1/2, and JNK can be regulated through other “CO sensors” [20,22].Figure 1


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

Chigaev A, Smagley Y, Sklar LA - BMC Immunol. (2014)

CO signaling cascade and small molecules used to modulate this pathway. Endogenous carbon monoxide is generated by heme oxygenase (HO). In cells CO reacts with hemeproteins. One of the CO receptors is the guanylyl cyclase (GC) that produces the intracellular messenger cyclic GMP (cGMP). cGMP interacts with the cGMP-dependent protein kinase (PKG), which phosphorylates multiple substrates, and participates in signal propagation. The carbon monoxide donor provides an exogenous source of CO. The natural HO substrate hemin increases CO production because conversion of heme into biliverdin represents the rate-limiting step in heme degradation [5]. The activator of soluble guanylyl cyclase binds to GC, and induces enzyme activation in the absence of CO. The cell permeable analog of cGMP diffuses across the plasma membrane, and thus, activates cGMP-dependent signaling.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4221689&req=5

Fig1: CO signaling cascade and small molecules used to modulate this pathway. Endogenous carbon monoxide is generated by heme oxygenase (HO). In cells CO reacts with hemeproteins. One of the CO receptors is the guanylyl cyclase (GC) that produces the intracellular messenger cyclic GMP (cGMP). cGMP interacts with the cGMP-dependent protein kinase (PKG), which phosphorylates multiple substrates, and participates in signal propagation. The carbon monoxide donor provides an exogenous source of CO. The natural HO substrate hemin increases CO production because conversion of heme into biliverdin represents the rate-limiting step in heme degradation [5]. The activator of soluble guanylyl cyclase binds to GC, and induces enzyme activation in the absence of CO. The cell permeable analog of cGMP diffuses across the plasma membrane, and thus, activates cGMP-dependent signaling.
Mentions: Endogenous CO is produced inside cells as a product of enzymatic degradation of heme catalyzed by the enzyme heme oxygenase (HO) that consists of two isoforms: HO-1 is inducible, and HO-2 is a constitutive form [20]. HO is localized in the cytosol and mitochondria [21]. The major source of heme for CO production is hemoglobin, and other hemeproteins (Figure 1). CO has been shown to stimulate soluble guanylyl cyclase, stimulate vasodilatation, block cell proliferation, participate in neural transmission, and inhibit platelet aggregation (see [20] and references therein). CO targets several heme-containing proteins and soluble guanylyl cyclase (sGC) was recognized as the first and the most studied “CO receptor”. Multiple physiological effects including vasodilatation and platelet aggregation are attributed to the cGMP/PKG-dependent arm of the CO signaling pathway. Other signaling molecules such as p38 MAPK, ERK1/2, and JNK can be regulated through other “CO sensors” [20,22].Figure 1

Bottom Line: Moreover, cell treatment with hemin, a natural source of CO, resulted in comparable VLA-4 ligand dissociation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and University of New Mexico Cancer Center, Albuquerque 87131, NM, USA. achigaev@salud.unm.edu.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus