The blood-brain barrier in systemic infection and inflammation

Abstract

The vascular blood-brain barrier is a highly regulated interface between the blood and brain. Its primary function is to protect central neurons while signaling the presence of systemic inflammation and infection to the brain to enable a protective sickness behavior response. With increasing degrees and duration of systemic inflammation, the vascular blood-brain barrier becomes more permeable to solutes, undergoes an increase in lymphocyte trafficking, and is infiltrated by innate immune cells; endothelial cell damage may occasionally occur. Perturbation of neuronal function results in the clinical features of encephalopathy. Here, the molecular and cellular anatomy of the vascular blood-brain barrier is reviewed, first in a healthy context and second in a systemic inflammatory context. Distinct from the molecular and cellular mediators of the blood-brain barrier's response to inflammation, several moderators influence the direction and magnitude at genetic, system, cellular and molecular levels. These include sex, genetic background, age, pre-existing brain pathology, systemic comorbidity, and gut dysbiosis. Further progress is required to define and measure mediators and moderators of the blood-brain barrier's response to systemic inflammation in order to explain the heterogeneity observed in animal and human studies.

Keywords: blood–brain barrier; infection; inflammation; moderation; signaling.

Fig. 1

Review methodology. A stepwise semi-automated approach was taken: an automated parent search was followed by a manual step, which then led to multiple daughters automated searches. The searches were last updated on July 18, 2021

Fig. 2

Vascular blood–brain barrier. Alternating layers of molecular (glycocalyx, basement membrane) and cellular (endothelial cells, pericytes, astrocytes) components form the blood–brain barrier. The five components are in bold typeface. The basement membrane is a single structure with a two-layer composition, since it is secreted by endothelial cells and astrocytes on either side

Fig. 3

Molecular components of the BBB. The glycocalyx coats the luminal surface of cerebral endothelial cells, protruding into the lumen in a frond-like manner. The basement membrane is laid down by endothelial cells and astrocytes. While the two types of the extracellular matrix are biochemically distinct, they are indistinguishable and fused into one entity during health, only to be separated when perivascular spaces develop as a result of the accumulation of cells or fluid. JAM: junctional adhesion molecule

Fig. 4

Vascular blood–brain barrier in health (upper panel) and during systemic inflammation (lower panel). The figure is divided into four vertical sections corresponding to the four types of BBB responses to increasing levels of systemic inflammation described in the text. In the first vertical section on the left, changes in signaling are exemplified by up- and downregulation of carriers and receptors. This is followed by increased cell and solute trafficking across the BBB, with enhanced transendothelial vesicular transport and tight junction breakdown, in the second and third vertical sections. A rolling lymphocyte has adhered to the endothelium, after which diapedesis into the potential perivascular space occurs, where the lymphocyte can crawl (step 1) or penetrate the glia limitans (step 2) to enter the brain parenchyma. The fourth vertical section illustrates structural damage to various components of the BBB, including the glycocalyx, basement membrane, endothelial cells, pericytes, and astrocytic endfeet

Fig. 5

Moderators of the blood–brain barrier response to systemic inflammation and infection. Moderators are highlighted in light orange and have colored arrows. Stratifying on these moderators or accounting for them as covariates will become important in future experimental or observational studies of BBB permeability