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TNF-a-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between I¿B-NF¿B and JAK-STAT3 pathways.

Authors: Matsumoto, Junichi  Dohgu, Shinya  Takata, Fuyuko  Machida, Takashi  Bölükbasi Hatip, Funda F  Hatip-Al-Khatib, Izzettin  Yamauchi, Atsushi  Kataoka, Yasufumi 
Citation: Matsumoto J, etal., Brain Res. 2018 Aug 1;1692:34-44. doi: 10.1016/j.brainres.2018.04.023. Epub 2018 Apr 24.
Pubmed: (View Article at PubMed) PMID:29702085
DOI: Full-text: DOI:10.1016/j.brainres.2018.04.023

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.

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CRRD Object Information
CRRD ID: 13800534
Created: 2018-10-15
Species: All species
Last Modified: 2018-10-15
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.