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

  • Brain Res. 2018 Aug 1:1692:34-44. doi: 10.1016/j.brainres.2018.04.023.
Junichi Matsumoto  1 ,  Shinya Dohgu  2 ,  Fuyuko Takata  3 ,  Takashi Machida  4 ,  Funda F Bölükbaşi Hatip  5 ,  Izzettin Hatip-Al-Khatib  6 ,  Atsushi Yamauchi  7 ,  Yasufumi Kataoka  8
Affiliations
  • 1. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: [email protected].
  • 2. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: [email protected].
  • 3. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: [email protected].
  • 4. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
  • 5. Department of Medical Pharmacology, Faculty of Medicine, Pamukkale University, Denizli, Turkey. Electronic address: [email protected].
  • 6. Department of Medical Pharmacology, Faculty of Medicine, Pamukkale University, Denizli, Turkey. Electronic address: [email protected].
  • 7. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: [email protected].
  • 8. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: [email protected].
PMID: 29702085 DOI: 10.1016/j.brainres.2018.04.023
Abstract

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.

Keywords
Interleukin-6; Microglia; NFκB; Pericyte; STAT3; Tumor necrosis factor-α.