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Dysfunction of brain pericytes in chronic neuroinflammation
#MMPMID26661157
Persidsky Y
; Hill J
; Zhang M
; Dykstra H
; Winfield M
; Reichenbach NL
; Potula R
; Mukherjee A
; Ramirez SH
; Rom S
J Cereb Blood Flow Metab
2016[Apr]; 36
(4
): 794-807
PMID26661157
show ga
Brain pericytes are uniquely positioned within the neurovascular unit to provide
support to blood brain barrier (BBB) maintenance. Neurologic conditions, such as
HIV-1-associated neurocognitive disorder, are associated with BBB compromise due
to chronic inflammation. Little is known about pericyte dysfunction during HIV-1
infection. We found decreased expression of pericyte markers in human brains from
HIV-1-infected patients (even those on antiretroviral therapy). Using primary
human brain pericytes, we assessed expression of pericyte markers (?1-integrin,
?-smooth muscle actin, platelet-derived growth factor-B receptor ?, CX-43) and
found their downregulation after treatment with tumor necrosis factor-? (TNF?) or
interleukin-1 ? (IL-1?). Pericyte exposure to virus or cytokines resulted in
decreased secretion of factors promoting BBB formation (angiopoietin-1,
transforming growth factor-?1) and mRNA for basement membrane components. TNF?
and IL-1? enhanced expression of adhesion molecules in pericytes paralleling
increased monocyte adhesion to pericytes. Monocyte migration across BBB models
composed of human brain endothelial cells and pericytes demonstrated a diminished
rate in baseline migration compared to constructs composed only of brain
endothelial cells. However, exposure to the relevant chemokine, CCL2, enhanced
the magnitude of monocyte migration when compared to BBB models composed of brain
endothelial cells only. These data suggest an important role of pericytes in BBB
regulation in neuroinflammation.
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