LPS antagonism of TGF-β signaling results in prolonged survival and activation of rat primary microglia
Article first published online: 17 DEC 2013
Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
Journal of Neurochemistry
Volume 129, Issue 1, pages 155–168, April 2014
How to Cite
- Issue published online: 21 MAR 2014
- Article first published online: 17 DEC 2013
- Accepted manuscript online: 20 NOV 2013 06:00AM EST
- Manuscript Accepted: 18 NOV 2013
- Manuscript Revised: 18 OCT 2013
- Manuscript Received: 5 JUL 2013
- Defense Medical Research Development Program
- smad signaling;
Accumulating evidence indicates that activated microglia contribute to the neuropathology involved in many neurodegenerative diseases and after traumatic injury to the CNS. The cytokine transforming growth factor-beta 1 (TGF-β1), a potent deactivator of microglia, should have the potential to reduce microglial-mediated neurodegeneration. It is therefore perplexing that high levels of TGF-β1 are found in conditions where microglia are chronically activated. We hypothesized that TGF-β1 signaling is suppressed in activated microglia. We therefore activated primary rat microglia with lipopolysaccharide (LPS) and determined the expression of proteins important to TGF-β1 signaling. We found that LPS treatment decreased the expression of the TGF-β receptors, TβR1 and TβR2, and reduced protein levels of Smad2, a key mediator of TGF-β signaling. LPS treatment also antagonized the ability of TGF-β to suppress expression of pro-inflammatory cytokines and to induce microglial cell death. LPS treatment similarly inhibited the ability of the TGF-β related cytokine, Activin-A, to down-regulate expression of pro-inflammatory cytokines and to induce microglial cell death. Together, these data suggest that microglial activators may oppose the actions of TGF-β1, ensuring continued microglial activation and survival that eventually may contribute to the neurodegeneration prevalent in chronic neuroinflammatory conditions.
We propose that LPS/TLR4 signaling interferes with key components in the TGF-β1 signaling pathway in primary microglia. As a result, the ability of TGF- β1 to exert anti-inflammatory effects is significantly reduced leading to prolonged survival of classically activated microglia. Identifying the mechanisms by which TGF- β1 signaling is targeted during microglia activation may yield novel strategies for deactivating chronically activated microglia.