LPS antagonism of TGF‐β signaling results in prolonged survival and activation of rat primary microglia

Abstract

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-b1), a potent deactivator of microglia, should have the potential to reduce microglial-mediated neurodegeneration. It is therefore perplexing that high levels of TGF-b1 are found in conditions where microglia are chronically activated. We hypothesized that TGF-b1 signaling is suppressed in activated microglia. We therefore activated primary rat microglia with lipopolysaccharide (LPS) and determined the expression of proteins important to TGF-b1 signaling. We found that LPS treatment decreased the expression of the TGF-b receptors, TbR1 and TbR2, and reduced protein levels of Smad2, a key mediator of TGF-b signaling. LPS treatment also antagonized the ability of TGF-b to suppress expression of pro-inflammatory cytokines and to induce microglial cell death. LPS treatment similarly inhibited the ability of the TGF-b 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-b1, ensuring continued microglial activation and survival that eventually may contribute to the neurodegeneration prevalent in chronic neuroinflammatory conditions.

Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain

“…In addition, microglia had decreased expression of TGFβR1 following LPS, and this downregulation was prolonged in aged microglia. This finding is consistent with reduced bioavailability of TGFβ because the presence of TGFβ augments TGFβR1 expression on microglia (Mitchell, et al, 2014). Importantly, aged microglia activated with LPS in vivo and treated ex vivo with TGFβ had decreased IL-1β expression after TGFβ treatment (data not shown).…”

Acetylcholine suppresses microglial inflammatory response via αnAChR to protect hippocampal neurons

“…Moreover, this study revealed that LPS treatment reduced the level of α7nAChR in microglia and that conversely ACh increased α7nAChR expression. Consistent with this, LPS not only reduces TGF-β receptors that are involved in signaling of anti-inflammatory cytokine TGFβ 1, but also impairs ability of TGF-β 1 to regulate expression of inflammatory mediators (Mitchell et al, 2014). Collectively, these results suggest ACh inhibition of neuroinflammation may require the presence of a key downstream receptor, such as α7nAChR, on microglia.…”

Mesenchymal Stem Cells Modulate the Functional Properties of Microglia via TGF-β Secretion

“…Classical NF‐kB consists of the p65/p50 heterodimer and is a pivotal regulator in inflammatory reactions, driving proinflammatory cytokine gene expression in microglia [34]. TGF‐β signaling, a potent deactivator of microglia, is thought to act as an anti‐inflammatory cytokine [9] and down‐regulates cytokine production in LPS‐stimulated microglia via Smad phosphorylation [35]. The relationship between CX3CL1 (fractalkine) and its receptor (CX3CR1) is tightly regulated in the brain.…”