Microglial Activation Results in Inhibition of TGF-β-Regulated Gene Expression

J Mol Neurosci. 2017 Dec;63(3-4):308-319. doi: 10.1007/s12031-017-0980-3. Epub 2017 Oct 5.


Chronic inflammation mediated by persistent microglial activation is associated with the pathogenesis of neurodegenerative diseases. The mechanisms underlying chronic microglial activation are poorly understood. We have previously shown that anti-inflammatory TGF-β signaling is inhibited in LPS-treated microglia. In this study, we assessed whether different disease-related microglial activators could downregulate TGF-β induction of gene expression. We examined the effects of amyloid β (Aβ) (1-42)- or heat-killed Listeria monocytogenes (HKLM) on the TGF-β-regulated gene expression in primary rat microglia. We found that Aβ (1-42) oligomers and HKLM, in addition to LPS, suppressed TGF-β-mediated induction of gene expression in part through reducing expression of TβR1 mRNA encoding the TGF-β receptor 1 in primary microglia. Aβ (1-42) and LPS also prevented induction of TGF-β-induced genes in primary microglia. Additionally, Aβ (1-42) rescued primary microglia from TGF-β-mediated cell death without increasing cell proliferation. Blockage of NFκB signaling, but not the ERK or IRF3 pathways, inhibited Aβ (1-42)- and LPS-mediated reduction of TβR1 mRNA. Finally, LPS and Aβ (1-42) induced transient upregulation of mRNAs encoding SnoN and Bambi, inhibitors of TGF-β signaling. Our data indicate that one mechanism through which activators may prolong microglial stimulation is through direct inhibition of anti-inflammatory signaling. A more detailed understanding of the interaction between inflammatory and anti-inflammatory pathways may reveal potential targets for ameliorating chronic inflammation and hence speed the development of therapeutics to address neurodegenerative diseases.

Keywords: Bambi; Microglia; Smad6; SnoN; TGF-β; TGF-β receptor 1.

MeSH terms

  • Amyloid beta-Peptides / toxicity
  • Animals
  • Cell Line
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Inflammation / metabolism
  • Interferon Regulatory Factor-3 / genetics
  • Interferon Regulatory Factor-3 / metabolism
  • Lipopolysaccharides / toxicity
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Microglia / drug effects
  • Microglia / metabolism*
  • Microglia / pathology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Peptide Fragments / toxicity
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*


  • Amyloid beta-Peptides
  • Bambi protein, rat
  • Interferon Regulatory Factor-3
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Peptide Fragments
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Skil_v1 protein, rat
  • Transcription Factors
  • Transforming Growth Factor beta
  • amyloid beta-protein (1-42)
  • Protein-Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Tgfbr1 protein, rat