Tumor necrosis factor and stroke: role of the blood-brain barrier

Abstract

The progression and outcome of stroke is affected by the intricate relationship between the blood-brain barrier (BBB) and tumor necrosis factor alpha (TNFalpha). TNFalpha crosses the intact BBB by a receptor-mediated transport system that is upregulated by CNS trauma and inflammation. In this review, we discuss intracellular trafficking and transcytosis of TNFalpha, regulation of TNFalpha transport after stroke, and the effects of TNFalpha on stroke preconditioning. TNFalpha can activate cytoprotective pathways by pretreatment or persistent exposure to low doses. This explains the paradoxical observation that transport of this proinflammatory cytokine improves the survival and function of hypoxic cells and of mice with stroke. The dual effects of TNFalpha may be related to differential regulation of TNFalpha trafficking downstream to TNFR1 and TNFR2 receptors. As we better understand how peripheral TNFalpha affects its own transport and modulates neuroregeneration, we may be in a better position to pharmacologically manipulate its regulatory transport system to treat stroke.

Fig.1

Schematic presentation of signaling pathways initiated by TNFR1. There are three cytoplasmic domains: TNFR1 internalization domain (TRID) which contains a YXXW motif; neutral sphingomyelinase domain (NSD), and the death domain (DD). TNFα binding to its receptors leads to recruitment of receptor-associated proteins. The outcome may be apoptosis resulting from caspase-8 action in the mitochondria or transcriptional induction of cell survival genes. Both cytotoxic and cytoprotective actions by ceramide and NFκB have been shown.

Fig.2

Cellular models of receptor-mediated endocytosis of TNFα and its potential exocytosis in BBB endothelial cells. In model 1, TNFR1 and TNFR2 both mediate internalization of TNFα, probably by clathrin-mediated pathways and targeting to vesicular transport. The ligand-receptor complex dissociates at a low pH in lysosomes or multivesicular body (MVB), and the receptor undergoes recycling or degradation. TNFα is freed and may diffuse across the basolateral membrane of the cell to reach the CNS. In model 2, TNFR2 is the main mediator of TNFα trafficking resulting from its relatively higher level of expression at the cell surface. The TNFα-R2 complex moves to the TNFα-R1 complex, possibly in the Golgi complex, and is sorted to the basolateral surface.

Fig.3

Once internalized by either receptor, TNFα undergoes two major fates: intracellular degradation or exocytosis. Even in non-polarized HEK293 cells, intact TNFα can be recovered in the exocytosis medium. TNFR2 induces more exocytosis but TNFR1 mediates a greater percent of intact TNFα.

Fig.4

Signaling and transport of leukemia inhibitory factor (LIF) can be modulated by TNFα in cultured endothelial cells. The expression of gp190 (specific receptor for LIF) is reduced, resulting from its accelerated degradation in lysosomes. The expression of gp130 (co-receptor and signal converter for LIF) is increased, resulting from transcriptional activation of NFκB. The overall outcome is reduced Stat3 activation and decreased LIF endocoytosis.

Fig.5

The actions of microcirculatory TNFα on the endothelial cells composing the BBB illustrate signal transmission across the BBB. The concentration of TNFα is elevated in a variety of metabolic, inflammatory, and hypoxic disorders. TNFα can be either transported across the BBB to act on the CNS directly, or it can induce secondary signals that in turn modulate CNS functions as preconditioning stimuli.