Sepsis-Associated Encephalopathy: The Blood-Brain Barrier and the Sphingolipid Rheostat

Abstract

Sepsis is not only a significant cause of mortality worldwide but has particularly devastating effects on the central nervous system of survivors. It is therefore crucial to understand the molecular structure, physiology, and events involved in the pathogenesis of sepsis-associated encephalopathy, so that potential therapeutic advances can be achieved. A key determinant to the development of this type of encephalopathy is morphological and functional modification of the blood-brain barrier (BBB), whose function is to protect the CNS from pathogens and toxic threats. Key mediators of pathologic sequelae of sepsis in the brain include cytokines, including TNF-α, and sphingolipids, which are biologically active components of cellular membranes that possess diverse functions. Emerging data demonstrated an essential role for sphingolipids in the pulmonary vascular endothelium. This raises the question of whether endothelial stability in other organs systems such as the CNS may also be mediated by sphingolipids and their receptors. In this review, we will model the structure and vulnerability of the BBB and hypothesize mechanisms for therapeutic stabilization and repair following a confrontation with sepsis-induced inflammation.

Keywords: blood–brain barrier; inflammation mediators; lipopolysaccharides; sepsis-associated encephalopathy; sphingosine.

Figure 1

Proposed mechanism for neurocognitive dysfunction in the CNS in sepsis. On the CNS side of blood–brain barrier, TNF-α drives multiple pathways for neuronal injury, induces apoptosis via NO, caspase pathways, and leads to cerebral edema.

Figure 2

Summary of diverse effects of LPS both during interface with BBB and within CNS: proposed mechanism representing the effects of lipopolysaccharide and TNF-α-at the blood–brain barrier (BBB) and the pathophysiologic sequelae leading to neurocognitive dysfunction. (A) LPS binds to its ligand, toll-like receptor 4 (TLR-4) at the endoluminal surface of brain microvascular endothelial cells. TNF-α-alpha concurrently binds to TNF-α-receptor. (B) Consequently, barrier integrity is lost, and molecular toxins that are normally prevented from entering are now able to migrate to the CNS interstitium, including TNF-α-alpha. TNF-α interacts with glial cells leading to neuronal injury, apoptosis, oligodendrocyte loss, and reactive astrogliosis. Neuronal injury and apoptosis in the hippocampus is a putative mechanism for delirium and protracted neurocognitive deficits. (C) On the basolateral surface of BBB endothelial cells, TRAF-2, TNF-α, and Sphk-1 form a complex that catalyzes the formation of sphingosine-1-phosphate (S-1-P) in the cytosol. S-1-P exits the cell via paracrine function and acts on S-1-P receptor on the luminal surface of the endothelium. Conformational change occurs in the transmembrane domains of the S-1-P receptor, ultimately activating GTPases RhoA and RAC. This results in actin and myosin re-arrangement and re-establishment of BBB integrity. (D) S-1-P also exerts paracrine activity on CNS neurons leading to cellular survival and prevention of apoptosis.

Figure 3

Cross talk between LPS and TNF receptor signaling: The blood–brain barrier (BBB) plays an integral role in the mechanism of neurocognitive injury in sepsis associated encephalopathy. Lipopolysaccharide decreases barrier functional integrity via structural changes in tight junctions and modifications in transendothelial transport. Sphingosine-1-phosphate (S-1-P) or an analogue is proposed to reinforce barrier integrity, potentially attenuating the neurocognitive sequelae of sepsis-associated encephalopathy.