Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors

Systemic Inhibition of Tissue-Nonspecific Alkaline Phosphatase Alters the Brain-Immune Axis in Experimental Sepsis

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

A Role for Endothelial Tissue-Nonspecific Alkaline Phosphatase in Blood-Tissue Barrier Health and Disease

Sepsis is a disorder that targets the microcirculation with significant effects at blood-tissue barriers such as the blood-brain barrier (BBB) and gut-vascular barrier (GVB). Intestinal barrier dysfunction is thought to be one of the most important contributors to multi-organ dysfunction in sepsis. As a common site of infection, the impaired gut allows the dissemination of bacteria, which exacerbates the disease pathophysiology, and can lead to long-term morbidity and mortality. The mechanisms that influence altered barrier permeability in the GVB in sepsis and other inflammatory disorders are not well understood. Tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity, which has been shown to be highly expressed on brain microvascular endothelial cells (BMECs), is a viable therapeutic target. TNAP activity is recognized as generally anti-inflammatory in sepsis-associated acute kidney injury (AKI) through mechanisms not well understood, and its role in health and disease at various tissue barriers has yet to be explored. One critical barrier to studying TNAP has been a lack of specific pharmacological and genetic tools. Therefore, we first sought to examine the effects of pharmacological and genetic manipulation of TNAP in experimental sepsis using novel techniques. Our central hypothesis was that pharmacological or genetic depletion of TNAP enzyme activity would result in exaggerated barrier permeability, increased inflammation, and impaired gut homeostasis in experimental sepsis. Initially, a genetic mouse model with over-expression of TNAP on endothelial cells (i.e., VE-cKO) revealed that TNAP-overexpression resulted in better clinical scores and increased survival at 48-hours post-sepsis. Additionally, mice with genetic deletion of TNAP on endothelial cells (i.e., VE-cKO) were used to determine a role for TNAP in GVB homeostasis. We found that VE-cKO septic mice display increased bacterial burden and increased parameters of gut dysbiosis at 8 days post-CLP, including a decreased Firmicutes:Bacteroidetes (F:B) ratio, decreased relative antimicrobial expression, and, at 3 days post-CLP, decreased levels of short-chain fatty acids (SCFAs). At 24 hours post-CLP, permeability to molecules ranging from 625 Da to 69 kDa is increased in VE-cKO ileum compared to Alplfl/fl littermate controls. The differences in permeability between intestinal segments demonstrates that TNAP’s enzyme activity may impact each region using different mechanisms. Ultimately, our results have shown that endothelial TNAP is protective during sepsis via two potential mechanisms: (1) decreasing bacterial burden and gut dysbiosis by 8 days post-CLP, and (2) decreasing intestinal permeability at 24 hours post-CLP. This work demonstrates a protective role for endothelial TNAP against GVB dysfunction which may be applicable to a number of inflammatory diseases

Tissue-Nonspecific Alkaline Phosphatase in Central Nervous System Health and Disease: A Focus on Brain Microvascular Endothelial Cells

Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme bound to the plasma membranes of numerous cells via a glycosylphosphatidylinositol (GPI) moiety. TNAP’s function is well-recognized from earlier studies establishing its important role in bone mineralization. TNAP is also highly expressed in cerebral microvessels; however, its function in brain cerebral microvessels is poorly understood. In recent years, few studies have begun to delineate a role for TNAP in brain microvascular endothelial cells (BMECs)—a key component of cerebral microvessels. This review summarizes important information on the role of BMEC TNAP, and its implication in health and disease. Furthermore, we discuss current models and tools that may assist researchers in elucidating the function of TNAP in BMECs

Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction

Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality. Recent studies suggest that children and adolescents have worse post-TBI outcomes and take longer to recover than adults. However, the pathophysiology and progression of TBI in the pediatric population are studied to a far lesser extent compared to the adult population. Common causes of TBI in children are falls, sports/recreation-related injuries, non-accidental trauma, and motor vehicle-related injuries. A fundamental understanding of TBI pathophysiology is crucial in preventing long-term brain injury sequelae. Animal models of TBI have played an essential role in addressing the knowledge gaps relating to pTBI pathophysiology. Moreover, a better understanding of clinical biomarkers is crucial to diagnose pTBI and accurately predict long-term outcomes. This review examines the current preclinical models of pTBI, the implications of pTBI on the brain\u27s vasculature, and clinical pTBI biomarkers. Finally, we conclude the review by speculating on the emerging role of the gut-brain axis in pTBI pathophysiology

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors