CXCL6 regulates cell permeability, proliferation, and apoptosis after ischemia–reperfusion injury by modulating Sirt3 expression via AKT/FOXO3a activation

ABSTRACT

Chemokine (C-X-C motif) ligand 6 (CXCL6), a member of the CXC chemokine family, reportedly mediates several processes such as inflammation, immunoreaction, cell growth, and metastasis through interaction with the chemokine receptors CXCR1 and CXCR2 in humans; further, CXCR1 and CXCR2 can promote repair and regeneration of organs or tissues after ischemia–reperfusion injury (IRI). In this study, we found that HIF-1α, CXCL6, and CXCR2 expression levels were elevated in human brain microvascular endothelial cells (HBMECs) after IRI, whereas silent information regulator of transcription (Sirt) 3 expression level had reduced. HIF-1α inhibition in an IRI model potently promoted HBMEC proliferation, accompanied by increased Sirt3 and decreased CXCL6/CXCR2 expression levels. CXCL6 knockdown in the IRI model significantly decreased HBMEC permeability and promoted HBMEC proliferation, concurrent with a decrease in apoptosis; it also increased Sirt3 expression levels and decreased CXCL6/CXCR2 protein and phosphorylated AKT (p-AKT) and class O of forkhead box (FOXO) 3a (p-FOXO3a) levels. In addition, CXCL6-induced HBMEC permeability and inhibition of HBMEC proliferation were counteracted by Sirt3 overexpression, and the AKT inhibitor LY294002 counteracted the effect of CXCL6 recombinant proteins on Sirt3, p-AKT, and p-FOXO3a expressions. These results suggest that CXCL6 and Sirt3 are downstream of HIF-1α and that CXCL6 regulatesHBMEC permeability, proliferation, and apoptosis after IRI by modulating Sirt3 expression via AKT/FOXO3a activation.

KEYWORDS:

• Ischemia–reperfusion injury
• CXCL6/CXCR2
• Sirt3
• HIF-1α
• AKT/FOXO3a pathway

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Authors’ contributions

TX and JFW conceived and designed the study. XLW, YQD, XXZ, KP and YD performed the experiments. TX and JFW wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Abbreviations

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Additional information

Funding

This work was supported by the Science Foundation of Shanghai Municipal Commission of Health and Family Planning [201640216].