Oncostatin-M-Reactive Pericytes Aggravate Blood–Brain Barrier Dysfunction by Activating JAK/STAT3 Signaling In Vitro

• Published in: Neuroscience Vol. 422; pp. 12 - 20
• Main Authors: Takata, Fuyuko, Dohgu, Shinya, Sakaguchi, Shinya, Sakai, Kenta, Yamanaka, Gaku, Iwao, Takuro, Matsumoto, Junichi, Kimura, Ikuya, Sezaki, Yume, Tanaka, Yoshie, Yamauchi, Atsushi, Kataoka, Yasufumi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01-12-2019
• Subjects: blood–brain barrier; brain endothelial cells; oncostatin M; pericytes; ruxolitinib; STAT3; BBB; oncostatin M; DMSO; CNS; brain endothelial cells; BSA; blood–brain barrier; ANOVA; ruxolitinib; PBS; BEC; IL; SDS; NFκB; pericytes; STAT3; Na-F; OSM; RBEC; gp; OSMR; MMP; STAT; JAK; TJ; TEER; GAPDH
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2019.10.014

The present findings demonstrate that (1) pericytes can respond to OSM and (2) OSM-reactive pericytes aggravate OSM-induced RBEC barrier dysfunction. These indirect aggravating effects of OSM-reactive pericytes are likely due to activated JAK/STAT3 signaling in pericytes. In a previous study, OSM was shown to directly act on RBECs, impairing RBEC barrier function by activating JAK/STAT3 signaling. This is shown in the right endothelial cell, indicated by the dotted line in the bottom panel of this figure.
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•Brain pericytes expressed OSM receptor proteins.•The presence of pericytes stimulated with OSM exacerbated the lowered brain endothelial barrier dysfunction by OSM.•Ruxolitinib blocked the BBB dysfunction aggravated by OSM-reactive pericytes via inhibiting JAK/STAT3 pathway.
Oncostatin M (OSM) is a cytokine of the interleukin (IL)-6 family members. It induces blood–brain barrier (BBB) dysfunction by activating Janus-activated kinase (JAK) and signal transducer and activator of transcription (STAT) 3 pathways in brain endothelial cells. Brain pericytes located around microvessels are one of the BBB constituents. Pericytes work as a boundary surface between the blood circulation and brain parenchyma, and their functions are altered under pathophysiological conditions, leading to BBB dysregulation. However, it remains unknown whether pericytes are associated with OSM-induced BBB dysfunction. We demonstrated that pericyte exposure to OSM (100 ng/mL) elevated phosphorylation of STAT3, a main OSM signaling pathway, and that pericytes expressed OSM receptors (OSMRs) including OSMRβ and glycoprotein 130. These results suggest that pericytes are able to respond to OSM. To determine the effects of OSM-reactive pericytes on BBB functions, rat brain endothelial cell (RBEC) monolayers were cultured with OSM-treated pericytes. The presence of pericytes exposed to 100 ng/mL of OSM for 48 h aggravated both the elevated permeability to sodium fluorescein and the lowered transendothelial electrical resistance which were induced by OSM in RBECs. This OSM-reactive pericyte-induced aggravation of lowered RBEC barrier function was reversed by ruxolitinib, a JAK inhibitor. These findings suggest that activated JAK/STAT3 signaling in pericytes contributes to OSM-produced BBB breakdown. Thus, OSM-reactive pericytes may have to be considered a characteristic machinery in the formation and progression of BBB breakdown under pathological conditions associated with increased OSM levels.