Neuroinflammation: a common pathway in CNS diseases as mediated at the blood-brain barrier

Abstract

The blood-brain barrier (BBB) is not simply a physical barrier but a regulatory interface between the central nervous system (CNS) and immune system. The BBB both affects and is affected by the immune system and connects at many levels with the CNS, including the following: (1) the BBB transports cytokines and secretes various substances with neuroinflammatory properties; (2) transporters are altered in disease states including traumatic injury, Alzheimer's disease and inflammatory processes; (3) cytokines and other immune secretions from the cells comprising the BBB are both constitutive and inducible; (4) immune cells are transported across the BBB by the highly regulated process termed diapedesis, which involves communication and interactions between the brain endothelial cells and the immune cells; (5) the neuroimmune system has various effects on the BBB, including modulation of important transport systems and in extreme pathological conditions even disruption of the BBB, and (6) the brain-to-blood efflux transporter P-glycoprotein is altered in inflammatory conditions, thus affecting drug delivery to the brain. In summary, the BBB is an interactive interface that regulates and defines many of the ways that the CNS and the immune system communicate with one another.

Fig. 1

An endocentric view of neuroinflammation. (1) Disruption of BBB integrity and disassembly of tight junctions permits transcellular (la) and paracellular (lb) entry of circulating components. (2) Circulating cytokines are transported across the BBB into the brain. (3) BBB endothelial cells are activated by circulating cytokines and other circulating inflammatory mediators, causing secretion of inflammatory mediators including cytokines into the brain parenchyma (3a) and alterations in the transport of substances across the BBB (3b). (4) Circulating immune cells cross the BBB via diapedesis by paracellular (4a) and transcellular (4b) pathways. (5) Circulating cytokines bypass the BBB by inflammatory activation of vagai afférents (5a) or inflammatory mediators crossing the leaky vasculature into circumventricular organs (CVOs; 5b), which are compartmentalized from the rest of the CNS by tanycytic barriers. PNS = Peripheral nervous system.

Fig. 2

Inflammatory regulation of LRP-1. Aß is transported across the BBB in the brain-to-blood direction (efflux) by the transporter LRP-1. In AD, LRP-1 is down-regulated at the BBB and decreased efflux of Aß occurs, contributing to Aß accumulation in the CNS. Inflammation induced by peripheral administration of LPS reduces Aß efflux via LRP-1, and this is inhibited by indomethacin. Diabetes causes downregulation of LRP-1 at the BBB. Both LPS and diabetes cause inflammation and oxidative stress in the CNS, which could potentially contribute to LRP-1 dysfunction.