Adenosine A2A Receptor Deficiency Up-Regulates Cystatin F Expression in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

Duan, Wei; Ran, Hong; Zhou, Zhujuan; He, Qifen; Zheng, Jie

doi:10.1371/journal.pone.0052566

Cited by 18 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several recent studies have indicated that CF was expressed in activated microglial cells, and CF expression was substantially up-regulated in regions of white matter rarefaction in various demyelinating diseases of the central nervous system 7 . Consistent with previous data, our in vitro experiment also showed that CF was highly expressed in activated microglial cells in white matter lesions, which were induced by chronic cerebral hypoperfusion 9 . The previously described results suggested that up-regulated CF expression may be associated with the exacerbation of white matter lesions after cerebral hypoperfusion-induced brain injury and other demyelinating diseases.…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with these findings, our previous study showed that CF was expressed in activated microglial cells in white matter lesions induced by chronic cerebral hypoperfusion. Importantly, A 2A R inactivation substantially increased CF production in activated microglial cells; moreover, the production of inflammatory cytokines was significantly increased in white matter lesions after chronic cerebral hypoperfusion 9 . These results suggested that CF expressed in activated microglia may be associated with the A 2A R effect on the neuroinflammatory response induced by chronic cerebral hypoperfusion.…”

Section: Introductionmentioning

confidence: 91%

See 1 more Smart Citation

Cystatin F involvement in adenosine A2A receptor-mediated neuroinflammation in BV2 microglial cells

Duan

Wang

Fan

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

Our previous studies have shown adenosine A2A R activation markedly promotes the expression of cystatin F (CF) and exacerbates the white matter lesions induced by hypoxic brain injuries. Thus, we hypothesized that CF was probably involved in neuroinflammation of activated microglia induced by A2A R activation. We transfected the BV2 cells with a CF shRNA vector and examined the production of pro-inflammatory cytokines in hypoxic-BV2 cells in which A2A R was activated or inactivated to confirm this hypothesis. Additionally, we also investigated the probable signaling pathways involved in modulation of A2A R activation on CF expression in hypoxia-activated BV2 cells. Activation of A2A R promoted CF expression, which was significantly increased after the low glucose and hypoxia treatments in BV2 cells. CF gene knockdown markedly inhibited the increase in the expression of pro-inflammatory cytokines induced by A2A R activation in hypoxic-BV2 cells. Furthermore, the increased expression of the CF induced by A2A R activation was remarkably inhibited in hypoxic-BV2 cells administrated with the PKA inhibitor H-89 and the PKC inhibitor staurosporine. Hence, these results indicate that hypoxia BV2 cells highly express CF, which is involved in A2A R activation-mediated neuroinflammation via the PKA/CREB and PKC/CREB or ERK1/2 signaling pathways.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 91%

Cystatin F involvement in adenosine A2A receptor-mediated neuroinflammation in BV2 microglial cells

Duan

Wang

Fan

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…To study the cellular pattern of Cst7 expression within the mouse brain, we interrogated the RNA-sequencing-based transcriptome database for mouse brain cortex cells [ 14 ]. This analysis revealed that Cst7 ranked at the 48 th percentile of expression of all mouse genes and that Cst7 transcripts were significantly enriched in microglia/macrophages as compared to other cell types of the brain cortex ( S2 Fig ), in line with the notion that Cst7 /Cystatin F is mainly expressed in immune cells, including microglia [ 29 , 30 ]. Of interest, transcriptomic analysis of different cell types of the human brain [ 15 ] showed that CST7 ranked t the 43 rd percentile of expression of all human genes and that CST7 transcripts are mainly detected in microglia/macrophages and endothelial cells ( S2 Fig ).…”

Section: Resultssupporting

confidence: 63%

Cystatin F is a biomarker of prion pathogenesis in mice

et al. 2017

View full text Add to dashboard Cite

Misfolding of the cellular prion protein (PrPC) into the scrapie prion protein (PrPSc) results in progressive, fatal, transmissible neurodegenerative conditions termed prion diseases. Experimental and epidemiological evidence point toward a protracted, clinically silent phase in prion diseases, yet there is no diagnostic test capable of identifying asymptomatic individuals incubating prions. In an effort to identify early biomarkers of prion diseases, we have compared global transcriptional profiles in brains from pre-symptomatic prion-infected mice and controls. We identified Cst7, which encodes cystatin F, as the most strongly upregulated transcript in this model. Early and robust upregulation of Cst7 mRNA levels and of its cognate protein was validated in additional mouse models of prion disease. Surprisingly, we found no significant increase in cystatin F levels in both cerebrospinal fluid or brain parenchyma of patients with Creutzfeldt-Jakob disease compared to Alzheimer’s disease or non-demented controls. Our results validate cystatin F as a useful biomarker of early pathogenesis in experimental models of prion disease, and point to unexpected species-specific differences in the transcriptional responses to prion infections.

show abstract

“…A broad spectrum of biological roles has been suggested for cystatins, including a role in protein catabolism, regulation of hormone processing and bone resorption, inflammation, antigen presentation, and T-cell dependent immune responses, and resistance to various bacterial and viral infections (Magister and Kos, 2013). Cystatins have been suggested to serve as modulators of the proteolytic system in several diseases (Magister and Kos, 2013), including demyelinating diseases (Ma et al, 2007, 2011; Sladkova et al, 2011; Duan et al, 2012). Cystatin F (Cys F), which belongs to the cystatin superfamily, is a cathepsin inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model

Liang

Zhang

et al. 2016

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

show abstract

Adenosine A2A Receptor Deficiency Up-Regulates Cystatin F Expression in White Matter Lesions Induced by Chronic Cerebral Hypoperfusion

Cited by 18 publications

References 40 publications

Cystatin F involvement in adenosine A2A receptor-mediated neuroinflammation in BV2 microglial cells

Cystatin F involvement in adenosine A2A receptor-mediated neuroinflammation in BV2 microglial cells

Cystatin F is a biomarker of prion pathogenesis in mice

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model

Contact Info

Product

Resources

About