The Neuroinflammatory Role of Pericytes in Epilepsy

Abstract

Pericytes are a component of the blood-brain barrier (BBB) neurovascular unit, in which they play a crucial role in BBB integrity and are also implicated in neuroinflammation. The association between pericytes, BBB dysfunction, and the pathophysiology of epilepsy has been investigated, and links between epilepsy and pericytes have been identified. Here, we review current knowledge about the role of pericytes in epilepsy. Clinical evidence has shown an accumulation of pericytes with altered morphology in the cerebral vascular territories of patients with intractable epilepsy. In vitro, proinflammatory cytokines, including IL-1β, TNFα, and IL-6, cause morphological changes in human-derived pericytes, where IL-6 leads to cell damage. Experimental studies using epileptic animal models have shown that cerebrovascular pericytes undergo redistribution and remodeling, potentially contributing to BBB permeability. These series of pericyte-related modifications are promoted by proinflammatory cytokines, of which the most pronounced alterations are caused by IL-1β, a cytokine involved in the pathogenesis of epilepsy. Furthermore, the pericyte-glial scarring process in leaky capillaries was detected in the hippocampus during seizure progression. In addition, pericytes respond more sensitively to proinflammatory cytokines than microglia and can also activate microglia. Thus, pericytes may function as sensors of the inflammatory response. Finally, both in vitro and in vivo studies have highlighted the potential of pericytes as a therapeutic target for seizure disorders.

Keywords: blood-brain barrier; cytokine; mural cells; neuroinflammation; pericytes.

Figure 1

Regulatory functions of pericytes. In the central nervous system (CNS), platelet-derived growth factor-beta subunit (PDGF-BB) is released by endothelial cells and binds to PDGFRβ at the cell surface of pericytes to promote pericyte vascularization within the blood–brain barrier (BBB). Secretion of angiopoietin-1 (ANGPT-1) and plasminogen activator inhibitor type 1 (PAI-1) from pericytes promotes the development of vascular endothelial cells and contributes to the maintenance of the BBB (1). Pericytes maintain neuronal health by secreting factors such as nerve growth factor (NGF), brain-derived nerve growth factor (BDNF), and pleiotrophin (2). Pericytes are involved in angiogenesis by secreting ANGPT-1 and erythropoietin (3) and produce a factor (Lama2) that facilitates the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (4).

Figure 2

In pathological conditions, pericytes generate various inflammatory factors. Pericytes secrete IL-6 that can polarize parenchymal microglia to a proinflammatory phenotype to activate microglia (1). The secretion of chemokines (CCL2, CXCL1, CXCL8, and CXCL10) by pericytes recruits leukocytes to the CNS parenchyma via the upregulation of ICAM-1 and VCAM-1 adhesion molecules on the endothelium (2). MMP-9 secretion stimulates the production and secretion of vascular endothelial growth factor (VEGF), resulting in endothelial dysfunction (3). Secretion of reactive oxygen species/reactive nitrogen species (ROS/RNS), nitric oxide (NO), and prostaglandins (PGE2) by pericytes lead to vasodilation and breaching of the blood–brain barrier. Pericytes themselves are morphologically altered by inflammatory mediators (4).

Figure 3

Schematic representation of the events linking pericytes to epilepsy. Status epilepticus leads to redistribution and remodeling of cerebrovascular pericytes, potentially contributing to blood–brain barrier permeability [2,28,29]. A significant clustering of microglia/macrophages around pericytes occurs one week after the attack, although pericyte proliferation is significantly increased as early as 72 h [29]. These series of pericyte-related modifications are promoted by proinflammatory cytokines, including IL-1β, TNFα, and IL-6. Alterations caused by IL-1β, which is one of the cytokines most deeply involved in the pathogenesis of epilepsy, were most pronounced. These pericyte-associated modifications and pericyte-microglia clustering may be facilitated by IL-1β [29], and pericyte-glial scarring with collagens III and IV process leaky capillaries during seizure progression [30]. Recurrent seizures can lead to pericytic injury with neurovascular decoupling and BBB dysfunction at the arterial and capillary levels. Moreover, capillary vasoconstriction is accompanied by a loss of mitochondrial integrity in pericytes [81]. In vitro and in vivo studies have highlighted the potential of pericytes as a therapeutic target for seizure disorders [28,30,32].