Microglia and the Blood-Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions

Abstract

Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood-brain barrier (BBB) function and their interaction with different cellular components of the BBB-endothelial cells, astrocytes and pericytes-are described. Here, we report the specific crosstalk of microglia with all the BBB cell types focusing in particular on the involvement of microglia in the modulation of BBB function in neuroinflammatory conditions that occur in conjunction with an acute event, such as a stroke, or in a slow neurodegenerative disease, such as Alzheimer's disease. The potential of microglia to exert a dual role, either protective or detrimental, depending on disease stages and environmental conditioning factors is also discussed.

Keywords: Alzheimer’s disease; BBB; astrocyte; endothelial cells; microglia; stroke.

Figure 1

Schematic representation of the Neurovascular Unit (NVU) structure and the reciprocal interaction among all components. The ECs, whose intracellular spaces are sealed by the TJs, are surrounded by mural cells (pericytes or smooth muscle cells). ECs and mural cells are enwrapped by the two basal laminas, which provide structural and functional support to the BBB. The astrocytic endfeet cover almost the whole blood vessel surface and make direct contact with ECs and mural cells. Neurons make contact with ECs and astrocytes, and their activity can regulate the vascular tone either directly on ECs or indirectly through astrocytes. Microglial processes make dynamic and transient contacts with the vasculature, astrocytes and neurons and contribute to the neurovascular coupling through P2Y12R.

Figure 2

Microglia and BBB function during stroke. During the hyperacute and acute phases of stroke, the damaged/dying neuronal cells release several soluble mediators (reported in the orange box) that drive microglia toward a pro-inflammatory M1-like phenotype. Such primed microglial cells release ROS, MMPs, miRNAs-charged EVs and pro-inflammatory cytokines that activate ECs and astrocytes. These latter, in turn, secrete other mediators (NO, glutamate, endothelin-1 (ET-1)) that further promote EC activation, TJs degradation and BBB disruption. Reactive astrocytes release further pro-inflammatory cytokines (e.g., CCL2, CXCL2) that promote the pro-inflammatory activity of microglia. Activated ECs express several adhesion molecules for leukocytes and secrete CXCL5 and MMP-3 that foster the pro-inflammatory status of microglia. In the chronic phase of stroke, ECs and astrocytes promote a beneficial anti-inflammatory M2-like phenotype in microglia, through the secretion of VEGF and TGFβ, respectively. The release of TGFβ from astrocytes is stimulated by IL-10 derived from M2-like microglia, in a positive feedback loop. In physiological conditions, ECs limit microglia priming through the expression of NO and CD200, to protect BBB integrity.

Figure 3

Time-dependent role of microglia in BBB function during development of AD. In the early stage of AD, microglial cells surround and engulf Aβ aggregates to limit their deposition. At later stages, Aβ accumulate in the brain and, by binding to CD33 receptor on microglia, reduce its clearance. Activation of microglia for prolonged periods leads to the secretion of pro-inflammatory cytokines and C1q that drives astrocyte activation and the release of C3, responsible for neuronal and EC damage. In addition, dysregulation of RAGE and LRP-1 and down-regulation of GLUT-1 in ECs lead to Aβ accumulation. Aβ aggregates can also bind to TLR4 on microglial surface and stimulate the NLRP3 inflammasome. Microglia-derived IL-1β stimulates astrocytes to release VEGF, which lead to the degradation of TJ proteins and BBB permeability. Endfeet of astrocytes surrounding Aβ plaques bear structural alterations. In the early stage of AD, astrocytes support the BBB, through the activation of heat-shock signaling (Dnajb1, Hspa1a, Hspa1b) and the down-regulation of NF-κB. Protective astrocytes release TGF β, which induce a protective phenotype in microglia.