Pericytes regulate vascular immune homeostasis in the CNS

Abstract

Pericytes regulate the development of organ-specific characteristics of the brain vasculature such as the blood–brain barrier (BBB) and astrocytic end-feet. Whether pericytes are involved in the control of leukocyte trafficking in the adult central nervous system (CNS), a process tightly regulated by CNS vasculature, remains elusive. Using adult pericyte-deficient mice (Pdgfbret/ret), we show that pericytes limit leukocyte infiltration into the CNS during homeostasis and autoimmune neuroinflammation. The permissiveness of the vasculature toward leukocyte trafficking in Pdgfbret/ret mice inversely correlates with vessel pericyte coverage. Upon induction of experimental autoimmune encephalomyelitis (EAE), pericyte-deficient mice die of severe atypical EAE, which can be reversed with fingolimod, indicating that the mortality is due to the massive influx of immune cells into the brain. Additionally, administration of anti-VCAM-1 and anti–ICAM-1 antibodies reduces leukocyte infiltration and diminishes the severity of atypical EAE symptoms of Pdgfbret/ret mice, indicating that the proinflammatory endothelium due to absence of pericytes facilitates exaggerated neuroinflammation. Furthermore, we show that the presence of myelin peptide-specific peripheral T cells in Pdgfbret/ret;2D2tg mice leads to the development of spontaneous neurological symptoms paralleled by the massive influx of leukocytes into the brain. These findings indicate that intrinsic changes within brain vasculature can promote the development of a neuroinflammatory disorder.

SARS-CoV-2 spike protein induces brain pericyte immunoreactivity in absence of productive viral infection

“…Several reports have demonstrated that pericytes actively contribute to the immune responses at the neurovascular interface by integrating signals from the periphery and the brain parenchyma [9, 10, 12]. Brain pericytes respond to immune challenge and modulate neuroimmune responses via various mechanisms including secretion of immune-active molecules, and regulation of leukocyte trafficking to the inflammation site [9, 12]. It has been recently proposed that pericyte dysfunction upon infection with SARS-CoV-2 causes microvasculature inflammation and injury [5].…”

“…Brain pericytes have been shown to contribute to the immune responses at the neurovascular interface by relaying signals from the periphery to the brain [9,11]. Pericytes contribute to neuroimmunomodulation via secretion of immune-active molecules, adoption of macrophage-like activity, presentation of antigens, and regulation of leukocyte trafficking across the cerebral vasculature [9,12]. Brain pericytes express basal levels of several ILs, cytokines and chemokines was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

“…Brain pericytes are specialized perivascular cells that play critical role in generating critical neurovascular functions that include blood-brain barrier (BBB) maintenance, and neurovascular coupling via cerebral blood flow (CBF) regulation [9, 10, 11]. Furthermore, pericytes possess immunoregulatory properties by acting as initial sensors of the inflammatory signals, which are subsequently relayed to the parenchyma via secretion of various inflammatory mediators, as well as by regulating the activation and infiltration of immune cells into the brain [9, 12]. Deregulation of pericyte function is directly implicated in the pathobiology of several neurological disorders, including cerebrovascular disorders [9, 13].…”

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

“…In multiple sclerosis (MS), the nature of the associated neurological deficits are highly dependent on the location of focal inflammatory immune cell infiltration and ensuing neural tissue lesions (Alvarez et al, 2015 ). When EAE, a mouse model of MS, was combined with the pdgf-b ret / ret model of pericyte deficiency, the regional immune infiltration correlated with regional pericyte loss (Torok et al, 2021 ). The local reduction in pericyte coverage drives an increased VCAM-1 and ICAM-1 expression on ECs, thereby facilitating trafficking of pro-inflammatory CD45 + leukocytes into the brain.…”

AAV-BR1 targets endothelial cells in the retina to reveal their morphological diversity and to deliver Cx43

“…Within the vascular branch, ECs tightly interact with other members of the neurovascular unit, such as pericytes and glia. These interactions are thought to be critical to vascular formation, integrity and homeostasis (Torok et al, 2021). As such, ECs can be also used as therapeutic targets to affect the function of surrounding glial cells and neurons (Y. H. Chen, Chang, & Davidson, 2009).…”