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Sustained anti-inflammatory effects of TGF-β1 on microglia/macrophages

Afsana Islam1, Mohammed Emamussalehin Choudhury1, Yuka Kigami1

  • 1Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.

Biochimica Et Biophysica Acta. Molecular Basis of Disease
|December 23, 2017
PubMed

Insights

Transforming growth factor-β1 (TGF-β1) persistently suppresses inflammation in ischemic brain injury by inhibiting microglia activation. This sustained effect, mediated by TGF-β1, offers a potential therapeutic target for neuroinflammation.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Ischemic brain injuries trigger inflammation via damage-associated molecular patterns (DAMPs) activating microglia/macrophages (MG/MPs) through Toll-like receptors.
  • Inducible nitric oxide synthase (iNOS) expression in MG/MPs peaks 3 days after reperfusion (dpr) in ischemic rat brains.
  • Transforming growth factor-β1 (TGF-β1) expression increases by 7 dpr, coinciding with a decrease in iNOS.

Purpose of the Study:

  • To investigate the sustained anti-inflammatory effects of TGF-β1 on microglial cells in the context of ischemic brain injury.
  • To elucidate the molecular mechanisms underlying TGF-β1's persistent inhibition of microglial activation.

Main Methods:

  • Transient middle cerebral artery occlusion in rats to induce ischemic brain injury.
  • Primary rat microglial cell cultures treated with TGF-β1 and lipopolysaccharide (LPS).
  • Measurement of nitric oxide (NO) release, IκB kinase (IKK) phosphorylation, IκB degradation, and NFκB nuclear translocation.
  • TGF-β1 knockdown and use of SB525334 (TGF-β1 receptor antagonist).

Main Results:

  • Transient TGF-β1 exposure resulted in sustained suppression of LPS-induced NO release from microglial cells, persisting for over 72 hours after TGF-β1 removal.
  • Boiled supernatants from ischemic brain tissue mimicked TGF-β1's sustained inhibitory effects, which were blocked by SB525334.
  • TGF-β1 treatment led to sustained inhibition of LPS-induced IκB degradation and NFκB nuclear translocation, effects abolished by SB525334.
  • Phosphorylated IKK levels in MG/MPs were high at 3 dpr and diminished by 7 dpr in ischemic lesions.

Conclusions:

  • Abundantly produced TGF-β1 in ischemic brains exerts sustained anti-inflammatory effects on microglial cells.
  • TGF-β1 persistently inhibits Toll-like receptor ligand-induced IκB degradation, thereby suppressing microglial activation.
  • These findings highlight TGF-β1's potential as a therapeutic agent for mitigating neuroinflammation post-ischemic brain injury.
Keywords:
Brain ischemiaInterferon regulatory factor 1Interleukin-4IκB kinaseNFκBiNOS

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