Abstract
Previously, it was demonstrated that the heme/heme oxygenase (HO)/carbon monoxide (CO) pathway inhibits neutrophil recruitment during the inflammatory response. Herein, we addressed whether the inhibitory effect of the HO pathway on neutrophil adhesion and migration involves the reduction of intracellular adhesion molecule type (ICAM)-1 and β2-integrin expression. Mice pretreated with a specific inhibitor of inducible HO (HO-1), zinc protoporphyrin (ZnPP) IX, exhibit enhanced neutrophil adhesion and migration induced by intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS). These findings are associated with an increase in ICAM-1 expression on mesentery venular endothelium. In accordance, HO-1 inhibition did not enhance LPS-induced neutrophil migration and adhesion in ICAM-1-deficient mice. Furthermore, the treatment with a CO donor (dimanganese decacarbonyl, DMDC) that inhibits adhesion and migration of the neutrophils, reduced LPS-induced ICAM-1 expression. Moreover, neither DMDC nor ZnPP IX treatments changed LPS-induced β2-integrin expression on neutrophils. The effect of CO on ICAM-1 expression seems to be dependent on soluble guanylate cyclase (sGC) activation, since 1H-(1,2,4)oxadiazolo (4,3-a)quinoxalin-1-one (sGC inhibitor) prevented the observed CO effects. Finally, it was observed that the nitric oxide (NO) anti-inflammatory effects on ICAM-1 expression appear to be indirectly mediated by HO-1 activation, since the inhibition of HO-1 prevented the inhibitory effect of the NO donor (S-nitroso-N-acetylpenicillamine) on LPS-induced ICAM-1 expression. Taken together, these results suggest that CO inhibits ICAM-1 expression on endothelium by a mechanism dependent on sGC activation. Thus, our findings identify the HO-1/CO/guanosine 3′5′-cyclic monophosphate pathway as a potential target for the development of novel pharmacotherapy to control neutrophil migration in inflammatory diseases.
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Abbreviations
- 1400W:
-
N-(3-(aminomethyl)-benzyl) acetamidine
- BVD:
-
biliverdin
- cGMP:
-
guanosine 3′5′-cyclic monophosphate
- CO:
-
carbon monoxide
- DMDC:
-
dimanganese decacarbonyl
- eNOS:
-
endothelial nitric oxide synthase
- fMLP:
-
formyl-methionyl-leucyl-phenylalanine
- HO:
-
heme oxygenase
- HO-1:
-
inducible heme oxygenase
- ICAM-1:
-
intracellular adhesion molecule type 1
- iNOS:
-
inducible nitric oxide synthase
- LPS:
-
Escherichia coli lipopolysaccharide
- NO:
-
nitric oxide
- NOS:
-
nitric oxide synthase
- ODQ:
-
[1H-(1,2,4)oxadiazolo (4,3-a)quinoxalin-1-one]
- Real-time RT-PCR:
-
real-time reverse transcription-polymerase chain reaction
- sGC:
-
soluble guanylate cyclase
- SNAP:
-
S-nitroso-N-acetylpenicillamine
- VCAM-1:
-
vascular adhesion molecule type 1
- ZnPP IX:
-
zinc protoporphyrin IX
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Acknowledgments
We thank Walter Miguel Turato for FACS analysis and Fabíola Leslie Mestriner, Ana Kátia dos Santos, Giuliana Bertozi Francisco, and Diva Amabile Montanha de Sousa for their excellent technical assistance. This work was supported by grants from Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Pesquisa (CNPq), and Fundação de Amparo à Pesquisa do Estado de Sao Paulo (FAPESP). Dr. A. Leyva provided English editing of the manuscript.
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Daniela Dal-Secco and Andressa Freitas contributed equally to this work.
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Dal-Secco, D., Freitas, A., Abreu, M.A. et al. Reduction of ICAM-1 expression by carbon monoxide via soluble guanylate cyclase activation accounts for modulation of neutrophil migration. Naunyn-Schmied Arch Pharmacol 381, 483–493 (2010). https://doi.org/10.1007/s00210-010-0500-2
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DOI: https://doi.org/10.1007/s00210-010-0500-2