Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

被引：25

作者：

Brichacek, Allison L. ^{[1
]}

Benkovic, Stanley A. ^{[2
]}

Chakraborty, Sreeparna ^{[1
]}

Nwafor, Divine C. ^{[2
]}

Wang, Wei ^{[2
]}

Jun, Sujung ^{[3
]}

Dakhlallah, Duaa ^{[1
]}

Geldenhuys, Werner J. ^{[4
]}

Pinkerton, Anthony B. ^{[5
]}

Millan, Jose Luis ^{[5
]}

Brown, Candice M. ^{[1
,2
]}

机构：

[1] West Virginia Univ, Ctr Basic & Translat Stroke Res, Rockefeller Neurosci Inst, Dept Microbiol Immunol & Cell Biol,Sch Med, Morgantown, WV 26506 USA

[2] West Virginia Univ, Ctr Basic & Translat Stroke Res, Rockefeller Neurosci Inst, Dept Neurosci,Sch Med, Morgantown, WV 26506 USA

[3] West Virginia Univ, Ctr Basic & Translat Stroke Res, Rockefeller Neurosci Inst, Dept Physiol & Pharmacol,Sch Med, Morgantown, WV 26506 USA

[4] West Virginia Univ, Sch Pharm, Ctr Basic & Translat Stroke Res, Dept Pharmaceut Sci,Rockefeller Neurosci Inst, Morgantown, WV 26506 USA

[5] Sanford Burnham Prebys Med Discovery Inst, La Jolla, CA USA

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

美国国家卫生研究院;

关键词：

VISUAL-CORTEX; POSTNATAL-DEVELOPMENT; MOUSE; EXPRESSION; PROMOTES; TNAP; IMMUNOSUPPRESSION; ECTONUCLEOTIDASES; LOCALIZATION; MECHANISMS;

D O I：

10.1038/s41598-019-55154-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25- and CD8 + Foxp3+ CD25- splenocyte T-cell populations compared to controls. Further evaluation of SBI-425's effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis.

引用

页数：19

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