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

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.

• Authors: Allison L Brichacek, Stanley A Benkovic, Sreeparna Chakraborty, Divine C Nwafor, Wei Wang, Sujung Jun, Duaa Dakhlallah, Werner J Geldenhuys, Anthony B Pinkerton, José Luis Millán, Candice M Brown
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 18788 (12 11 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31827139 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Immunosuppressive Agents
• SBI-425
• Sulfonamides
• Niacinamide
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (antagonists & inhibitors, physiology)
• Animals
• Astrocytes (drug effects)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (drug effects, enzymology, immunology)
• Endothelial Cells (drug effects)
• Female
• Immunosuppressive Agents (metabolism, pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia (drug effects)
• Niacinamide (analogs & derivatives, metabolism, pharmacology, therapeutic use)
• Sepsis (drug therapy, immunology)
• Sulfonamides (metabolism, pharmacology, therapeutic use)
• T-Lymphocytes (immunology)