A role for human brain pericytes in neuroinflammation

Abstract

BackgroundBrain inflammation plays a key role in neurological disease. Although much research has been conducted investigating inflammatory events in animal models, potential differences in human brain versus rodent models makes it imperative that we also study these phenomena in human cells and tissue.MethodsPrimary human brain cell cultures were generated from biopsy tissue of patients undergoing surgery for drug-resistant epilepsy. Cells were treated with pro-inflammatory compounds IFNγ, TNFα, IL-1β, and LPS, and chemokines IP-10 and MCP-1 were measured by immunocytochemistry, western blot, and qRT-PCR. Microarray analysis was also performed on late passage cultures treated with vehicle or IFNγ and IL-1β.ResultsEarly passage human brain cell cultures were a mixture of microglia, astrocytes, fibroblasts and pericytes. Later passage cultures contained proliferating fibroblasts and pericytes only. Under basal culture conditions all cell types showed cytoplasmic NFκB indicating that they were in a non-activated state. Expression of IP-10 and MCP-1 were significantly increased in response to pro-inflammatory stimuli. The two chemokines were expressed in mixed cultures as well as cultures of fibroblasts and pericytes only. The expression of IP-10 and MCP-1 were regulated at the mRNA and protein level, and both were secreted into cell culture media. NFκB nuclear translocation was also detected in response to pro-inflammatory cues (except IFNγ) in all cell types. Microarray analysis of brain pericytes also revealed widespread changes in gene expression in response to the combination of IFNγ and IL-1β treatment including interleukins, chemokines, cellular adhesion molecules and much more.ConclusionsAdult human brain cells are sensitive to cytokine challenge. As expected ‘classical’ brain immune cells, such as microglia and astrocytes, responded to cytokine challenge but of even more interest, brain pericytes also responded to such challenge with a rich repertoire of gene expression. Immune activation of brain pericytes may play an important role in communicating inflammatory signals to and within the brain interior and may also be involved in blood brain barrier (BBB) disruption . Targeting brain pericytes, as well as microglia and astrocytes, may provide novel opportunities for reducing brain inflammation and maintaining BBB function and brain homeostasis in human brain disease.

Pericytes of the neurovascular unit: key functions and signaling pathways

“…The role of pericytes in neuroinflammation has also been suggested by in vitro studies 40,41 . Altogether, these findings suggest that immune activation of brain pericytes may contribute to communicating inflammatory signals within the NVU.…”

Cerebral microvascular pericytes and neurogliovascular signaling in health and disease

“…Pericytes also present inflammatory cues and release inflammatory mediators including IL-1ș, IL-6, TNFȘ, ROS, NO and matrix metalloproteinases when activated with immune stimuli (Jansson et al, 2014;Kovac et al, 2011;Proebstl et al, 2012;Stark et al, 2013;Wang et al, 2012). They can even assume a macrophage phenotype and migrate to perivascular space, becoming indistinguishable from resident macrophages and activated microglia (Balabanov et al, 1996;Hurtado-Alvarado et al, 2014;Ozen et al, 2012;Pieper et al, 2014;Thomas, 1999).…”

Role of nucleotide‐binding oligomerization domain 1 (NOD1) in pericyte‐mediated vascular inflammation

“…In contrast to the numerous studies assessing the crosstalk among brain endothelial cells, astrocytes and microglia during inflammation, little is known about the role played by the brain microvascular pericyte. In fact, the response of brain pericytes to pro‐inflammatory stimuli has only been addressed in the last few years 2, 3, 4. In a pioneering work, Kovac et al .…”