2. Academic Validation
  3. Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis

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

  • Sci Rep. 2019 Dec 11;9(1):18788. doi: 10.1038/s41598-019-55154-2.
Allison L Brichacek 1,  Stanley A Benkovic 2,  Sreeparna Chakraborty 1,  Divine C Nwafor 2,  Wei Wang 2,  Sujung Jun 3,  Duaa Dakhlallah 1,  Werner J Geldenhuys 4,  Anthony B Pinkerton 5,  José Luis Millán 5,  Candice M Brown 6 7
Affiliations

Affiliations

  • 1 Department of Microbiology, Immunology, and Cell Biology, School of Medicine, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
  • 2 Department of Neuroscience, School of Medicine, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
  • 3 Department of Physiology and Pharmacology, School of Medicine, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
  • 4 Department of Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.
  • 5 Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 6 Department of Microbiology, Immunology, and Cell Biology, School of Medicine, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA. cdbrown2@hsc.wvu.edu.
  • 7 Department of Neuroscience, School of Medicine, Center for Basic and Translational Stroke Research, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA. cdbrown2@hsc.wvu.edu.
PMID: 31827139 DOI: 10.1038/s41598-019-55154-2
Abstract

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.

Figures
Products