Autocrine Interleukin-10 Mediates Glucagon-Like Peptide-1 Receptor-Induced Spinal Microglial β-Endorphin Expression

• Published in: The Journal of neuroscience 2017-11, Vol.37 (48), p.11701-11714
• Main Authors: Wu, Hai-Yun, Tang, Xue-Qi, Mao, Xiao-Fang, Wang, Yong-Xiang
• Format: Article
• Language: English
• Subjects: Activation; Animals; Animals, Newborn; Autocrine Communication - drug effects; Autocrine Communication - physiology; Autocrine signalling; beta-Endorphin - biosynthesis; beta-Endorphin - genetics; Cells, Cultured; Cyclic AMP response element-binding protein; Cytokines; Dose-Response Relationship, Drug; Endorphins; Exenatide; Gene Expression; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - biosynthesis; Glucagon-Like Peptide-1 Receptor - genetics; Inflammation; Injection; Interleukin 10; Interleukin 4; Interleukin 6; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-10 - pharmacology; Kinases; Male; Markers; Microglia; Microglia - drug effects; Microglia - metabolism; Neuropathy; Neuroprotection; Pain perception; Peptides - pharmacology; Phosphorylation; Protein kinase A; Rats; Rats, Wistar; Receptor mechanisms; Receptors; Rodents; Signal transduction; siRNA; Spinal Cord - cytology; Spinal Cord - drug effects; Spinal Cord - metabolism; Stat3 protein; Tumor necrosis factor-α; Venoms - pharmacology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1799-17.2017

The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial β-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced β-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1β, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1β, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and β-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated β-endorphin expression in cultured primary microglia, whereas treatment with β-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of β-endorphin and and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38β, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial β-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and β-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated β-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38β/CREB and subsequent IL-10 receptor/STAT3 signal pathways. Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor β-endorphin from microglia. GLP-1 receptor agonism induces β-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and β-endorphin expression subsequently through the Gs-cAMP/PKA/p38β/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.