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The binding of PKCε and MEG2 to STAT3 regulates IL-6-mediated microglial hyperalgesia during inflammatory pain.
- Source :
-
FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Apr 30; Vol. 38 (8), pp. e23590. - Publication Year :
- 2024
-
Abstract
- Studies have suggested that microglial IL-6 modulates inflammatory pain; however, the exact mechanism of action remains unclear. We therefore hypothesized that PKCε and MEG2 competitively bind to STAT3 and contribute to IL-6-mediated microglial hyperalgesia during inflammatory pain. Freund's complete adjuvant (FCA) and lipopolysaccharide (LPS) were used to induce hyperalgesia model mice and microglial inflammation. Mechanical allodynia was evaluated using von Frey tests in vivo. The interaction among PKCε, MEG2, and STAT3 was determined using ELISA and immunoprecipitation assay in vitro. The PKCε, MEG2, t-STAT3, pSTAT3 <superscript>Tyr705</superscript> , pSTAT3 <superscript>Ser727</superscript> , IL-6, GLUT3, and TREM2 were assessed by Western blot. IL-6 promoter activity and IL-6 concentration were examined using dual luciferase assays and ELISA. Overexpression of PKCε and MEG2 promoted and attenuated inflammatory pain, accompanied by an increase and decrease in IL-6 expression, respectively. PKCε displayed a stronger binding ability to STAT3 when competing with MEG2. STAT3 <superscript>Ser727</superscript> phosphorylation increased STAT3 interaction with both PKCε and MEG2. Moreover, LPS increased PKCε, MEG2, pSTAT3 <superscript>Tyr705</superscript> , pSTAT3 <superscript>Ser727</superscript> , IL-6, and GLUT3 levels and decreased TREM2 during microglia inflammation. IL-6 promoter activity was enhanced or inhibited by PKCε or MEG2 in the presence of STAT3 and LPS stimulation, respectively. In microglia, overexpression of PKCε and/or MEG2 resulted in the elevation of tSTAT3, pSTAT3 <superscript>Tyr705</superscript> , pSTAT3 <superscript>Ser727</superscript> , IL-6, and TREM2, and the reduction of GLUT3. PKCε is more potent than MEG2 when competitively binding to STAT3, displaying dual modulatory effects of IL-6 production, thus regulating the GLUT3 and TREM2 in microglia during inflammatory pain sensation.<br /> (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Subjects :
- Animals
Male
Mice
Freund's Adjuvant
Lipopolysaccharides toxicity
Lipopolysaccharides pharmacology
Membrane Glycoproteins metabolism
Membrane Glycoproteins genetics
Mice, Inbred C57BL
Pain metabolism
Phosphorylation
Protein Binding
Receptors, Immunologic metabolism
Receptors, Immunologic genetics
Protein Tyrosine Phosphatases, Non-Receptor metabolism
Hyperalgesia metabolism
Inflammation metabolism
Interleukin-6 metabolism
Interleukin-6 genetics
Microglia metabolism
Protein Kinase C-epsilon metabolism
Protein Kinase C-epsilon genetics
STAT3 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-6860
- Volume :
- 38
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publication Type :
- Academic Journal
- Accession number :
- 38656553
- Full Text :
- https://doi.org/10.1096/fj.202300152RR