TNF-α-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IκB-NFκB and JAK-STAT3 pathways

• Published in: Brain research 2018-08, Vol.1692, p.34-44
• Main Authors: Matsumoto, Junichi, Dohgu, Shinya, Takata, Fuyuko, Machida, Takashi, Bölükbaşi Hatip, Funda F., Hatip-Al-Khatib, Izzettin, Yamauchi, Atsushi, Kataoka, Yasufumi
• Format: Article
• Language: English
• Subjects: Animals; Brain - cytology; Cells, Cultured; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Gene Expression Regulation - drug effects; I-kappa B Proteins - metabolism; Interleukin-6; Interleukin-6 - metabolism; Mice; Microglia; Microglia - drug effects; NF-kappa B; NFκB; Pericyte; Pericytes - drug effects; Rats; Rats, Wistar; RNA, Messenger - metabolism; Signal Transduction - drug effects; STAT3; STAT3 Transcription Factor - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2018.04.023

•TNF-α induced activation of the JAK-STAT3 and IκB-NFκB pathways in pericytes.•TNF-α stimulated pericytes to release IL-6 via cooperation of these two pathways.•Pericyte-derived IL-6 increased iNOS mRNA expression in BV-2 microglia.•Pericytes-triggered microglial activation may be involved in brain inflammation. Interleukin (IL)-6 is an important mediator of neurovascular dysfunction, neurodegeneration and/or neuroinflammation. We previously reported that brain pericytes released higher levels of IL-6 than did glial cells (astrocytes and microglia) in response to tumor necrosis factor (TNF)-α. Moreover, pericytes stimulated with TNF-α enhanced activation of BV-2 microglia. In this study, we investigated the mechanisms of TNF-α mediated induction of IL-6 release from brain pericytes and astrocytes and whether pericyte-derived IL-6 would facilitate activation of BV-2 microglia. Using rat brain pericyte and astrocyte primary cultures and pharmacological inhibitors, we found that, TNF-α induced the highest levels of IL-6 release from pericytes by activating the inhibitor kappa B (IκB)-nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT)3 pathways. STAT3 contributed to TNF-α induced nuclear translocation of phospho-NFκB in pericytes. TNF-α-induced IL-6 release in astrocytes was mediated by NFκB but not by STAT3. The presence of pericytes amplified TNF-α-induced iNOS mRNA expression in BV-2 microglia. This effect was blocked by a neutralizing antibody for IL-6. These findings indicated that crosstalk between the IκB-NFκB and JAK-STAT3 pathways is a pericyte specific mechanism, not occurring in astrocytes, for TNF-α-induced IL-6 release. IL-6 derived from pericytes enhanced microglial activation. Our findings increase understanding of the role of pericyte-microglia crosstalk in the brain under neuroinflammatory conditions and suggest a potentially attractive therapeutic target for brain inflammation.