Abstract
BackgroundMultiple sclerosis (MS) is a neurodegenerative condition of the central nervous system (CNS). It is associated with blood–brain barrier (BBB) breakdown and intravasation of leukocytes, particularly monocyte-derived macrophages, into the CNS. Pericytes are mural cells that are encased within the basement membrane of vasculature, and they contribute functionally to the neurovascular unit. These cells play an important role in maintaining BBB integrity and CNS homeostasis. However, the critical role of pericytes in mediating inflammation in MS or its models is unclear. Whether pericytes infiltrate into the CNS parenchyma in MS also needs clarification.MethodsCNS samples from the experimental autoimmune encephalomyelitis (EAE) mouse model of MS were collected at different time points for immunohistochemical analysis of pericytes along the inflamed vasculature. These findings were validated using MS brain specimens, and further analysis of pericyte involvement in inflammation was carried out by culturing primary pericytes and macrophages. Multiplex ELISA, transmigration assay and real-time PCR were used to study the inflammatory potential of pericytes in cultures.ResultsWe found that pericytes exhibit a heterogenous morphology, with notable elongation in the inflamed perivascular cuffs of EAE. This was manifested by a decrease in pericyte density but an increase in the coverage by pericytes along the vasculature. Chondroitin sulfate proteoglycans (CSPGs), a family of extracellular matrix proteins enriched within inflamed perivascular cuffs, elevated levels of pro-inflammatory chemokines/cytokines in pericytes in culture. Importantly, pericytes stimulated with CSPGs enhanced macrophage migration. We did not detect pericytes in the CNS parenchyma during EAE, and this was corroborated in MS brain samples.ConclusionsOur data suggest that pericytes seek to restore the BBB through increased coverage, but that their exposure to CSPGs prompt their facilitation of macrophages to enter the CNS to elevate neuroinflammation in EAE and MS.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory-neurodegenerative condition that affects the central nervous system (CNS)
The brain has the highest ratio of pericytes to endothelial cells, which highlights the significance of pericytes in contributing to CNS homeostasis [5]
A recent study shows that pericyte-deficient (Pdgfbret/ ret) adult mice have increased transmigration of leukocytes into the brain resulting in enhanced disease severity of experimental autoimmune encephalomyelitis (EAE), an inflammatory model of MS [11]
Summary
MS is a chronic inflammatory-neurodegenerative condition that affects the central nervous system (CNS). Other studies suggest that extracellular matrix (ECM) components including fibronectin and collagen-I may influence pericyte morphology, migration, and proliferation, while heparan sulfate proteoglycans have inhibitory effects [13] In this regard, the influence of another major ECM component, chondroitin sulphate proteoglycans (CSPGs), and their dynamic interactions with pericytes with regard to their influence on BBB integrity, inflammatory responses, and facilitating leukocyte migration are not explored. Multiple sclerosis (MS) is a neurodegenerative condition of the central nervous system (CNS) It is associated with blood–brain barrier (BBB) breakdown and intravasation of leukocytes, monocyte-derived macrophages, into the CNS. Pericytes are mural cells that are encased within the basement membrane of vasculature, and they contribute functionally to the neurovascular unit These cells play an important role in maintaining BBB integrity and CNS homeostasis. Whether pericytes infiltrate into the CNS parenchyma in MS needs clarification
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