Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia

Rui Wang, Shu Ting Wang, Yu Di Wang, Gang Wu, Yan Du, Man Qing Qian, Xing Guang Liang, Mahmoud H. Elbatreek, Hong Yu Yang, Zhi Rong Liu, Kohji Fukunaga, Jian Xiang Liu, Ying Mei Lu

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 μM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia.

Original languageEnglish
Pages (from-to)445-454
Number of pages10
JournalNeuroReport
Volume27
Issue number6
DOIs
Publication statusPublished - 2016 Apr 13
Externally publishedYes

Keywords

  • Brain hypoperfusion
  • Cognitive dysfunction
  • HO-1
  • Neuronal cell death
  • TLR4

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Wang, R., Wang, S. T., Wang, Y. D., Wu, G., Du, Y., Qian, M. Q., Liang, X. G., Elbatreek, M. H., Yang, H. Y., Liu, Z. R., Fukunaga, K., Liu, J. X., & Lu, Y. M. (2016). Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia. NeuroReport, 27(6), 445-454. https://doi.org/10.1097/WNR.0000000000000561