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p38β Mitogen-Activated Protein Kinase Signaling Mediates Exenatide-Stimulated Microglial β-Endorphin Expression
Hai-Yun Wu1, Xiao-Fang Mao1, Hui Fan1
1King's Laboratory, Shanghai Jiao Tong University School of Pharmacy, Shanghai, China.
Abstract:
Recent discoveries established that activation of glucagon-like peptide-1 receptors (GLP-1Rs) mediates neuroprotection and antinociception through microglial β-endorphin expression. This study aimed to explore the underlying signaling mechanisms of microglial β-endorphin. GLP-1Rs and β-endorphin were coexpressed in primary cultures of microglia. Treatment with the GLP-1R agonist exenatide concentration-dependently stimulated microglial expression of the β-endorphin precursor gene proopiomelanocortin (POMC) and peptides, with EC50 values of 4.1 and 7.5 nM, respectively. Exenatide also significantly increased intracellular cAMP levels and expression of p-protein kinase A (PKA), p-p38, and p-cAMP response element binding protein (CREB) in cultured primary microglia. Furthermore, exenatide-induced microglial expression of POMC was completely blocked by reagents that specifically inhibit adenylyl cyclase and activation of PKA, p38, and CREB. In addition, knockdown of p38β (but not p38α) using short interfering RNA (siRNA) eliminated exenatide-induced microglial p38 phosphorylation and POMC expression. In contrast, lipopolysaccharide increased microglial activation of p38, and knockdown of p38α (but not p38β) partially suppressed expression of proinflammatory factors (including tumor necrosis factor-α, interleukin-1β, and interleukin-6). Exenatide-induced phosphorylation of p38 and CREB was also totally blocked by the PKA inhibitor and siRNA/p38β, but not by siRNA/p38α Seven-day intrathecal injections of siRNA/p38β (but not siRNA/p38α) completely blocked exenatide-induced spinal p38 activation, β-endorphin expression, and mechanical antiallodynia in rats with established neuropathy, although siRNA/p38β and siRNA/p38α were not antiallodynic. To our knowledge, our results are the first to show a causal relationship between the PKA-dependent p38β mitogen-activated protein kinase/CREB signal cascade and GLP-1R agonism-mediated microglial β-endorphin expression. The differential role of p38α and p38β activation in inflammation and nociception was also highlighted.
Insights
Glucagon-like peptide-1 receptor (GLP-1R) activation stimulates microglial beta-endorphin production via a PKA-dependent p38β/CREB pathway, offering neuroprotection and pain relief. This highlights distinct roles for p38 isoforms in inflammation and nociception.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Glucagon-like peptide-1 receptors (GLP-1Rs) mediate neuroprotection and antinociception.
- Microglial beta-endorphin expression is a key mediator of GLP-1R's neuroprotective effects.
- The precise signaling pathways underlying microglial beta-endorphin regulation remain unclear.
Purpose of the Study:
- To elucidate the intracellular signaling mechanisms by which GLP-1R activation induces microglial beta-endorphin expression.
- To investigate the roles of protein kinase A (PKA), p38 mitogen-activated protein kinase (MAPK), and cAMP response element binding protein (CREB) in this pathway.
- To differentiate the roles of p38α and p38β isoforms in GLP-1R signaling and microglial inflammatory responses.
Main Methods:
- Primary microglial cultures treated with GLP-1R agonist exenatide.
- Measurement of proopiomelanocortin (POMC) gene and peptide expression.
- Assessment of intracellular cAMP levels, PKA, p38, and CREB phosphorylation.
- Pharmacological inhibition and short interfering RNA (siRNA) knockdown of signaling molecules.
- In vivo studies using intrathecal siRNA injections in a rat neuropathy model.
Main Results:
- Exenatide stimulated microglial POMC expression and beta-endorphin release concentration-dependently.
- Exenatide increased cAMP, PKA, p38, and CREB phosphorylation, which were blocked by adenylyl cyclase and PKA inhibitors.
- Knockdown of p38β, but not p38α, abolished exenatide-induced p38 phosphorylation and POMC expression.
- In vivo, p38β knockdown blocked exenatide-induced spinal beta-endorphin expression and antiallodynia in neuropathic rats.
Conclusions:
- GLP-1R agonism activates a PKA-dependent signaling cascade involving p38β MAPK and CREB to enhance microglial beta-endorphin expression.
- This pathway is crucial for the antinociceptive effects of GLP-1R activation in neuropathic pain.
- p38α and p38β isoforms exhibit differential roles in microglial inflammatory responses and nociception.
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