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Metabolic regulation of RA macrophages is distinct from RA fibroblasts and blockade of glycolysis alleviates inflammatory phenotype in both cell types.
- Source :
-
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Dec; Vol. 78 (23), pp. 7693-7707. Date of Electronic Publication: 2021 Oct 27. - Publication Year :
- 2021
-
Abstract
- Recent studies have shown the significance of metabolic reprogramming in immune and stromal cell function. Yet, the metabolic reconfiguration of RA macrophages (MΦs) is incompletely understood during active disease and in crosstalk with other cell types in experimental arthritis. This study elucidates a distinct regulation of glycolysis and oxidative phosphorylation in RA MΦs compared to fibroblast (FLS), although PPP (Pentose Phosphate pathway) is similarly reconfigured in both cell types. 2-DG treatment showed a more robust impact on impairing the RA M1 MΦ-mediated inflammatory phenotype than IACS-010759 (IACS, complexli), by reversing ERK, AKT and STAT1 signaling, IRF8/3 transcription and CCL2 or CCL5 secretion. This broader inhibitory effect of 2-DG therapy on RA M1 MΦs was linked to dysregulation of glycolysis (GLUT1, PFKFB3, LDHA, lactate) and oxidative PPP (NADP conversion to NADPH), while both compounds were ineffective on oxidative phosphorylation. Distinctly, in RA FLS, 2-DG and IACS therapies constrained LPS/IFNγ-induced AKT and JNK signaling, IRF5/7 and fibrokine expression. Disruption of RA FLS metabolic rewiring by 2-DG or IACS therapy was accompanied by a reduction of glycolysis (HIF1α, PFKFB3) and suppression of citrate or succinate buildup. We found that 2-DG therapy mitigated CIA pathology by intercepting joint F480 <superscript>+</superscript> iNOS <superscript>+</superscript> MΦ, Vimentin <superscript>+</superscript> fibroblast and CD3 <superscript>+</superscript> T cell trafficking along with downregulation of IRFs and glycolytic intermediates. Surprisingly, IACS treatment was inconsequential on CIA swelling, cell infiltration, M1 and Th1/Th17 cytokines (IFN-γ/IL-17) and joint glycolytic mediators. Collectively, our results indicate that blockade of glycolysis is more effective than inhibition of complex 1 in CIA, in part due to its effectiveness on the MΦ inflammatory phenotype.<br /> (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Subjects :
- Animals
Antimetabolites pharmacology
Arthritis, Experimental physiopathology
Cell Movement
Cytokines
Fibroblasts drug effects
Fibroblasts metabolism
Fibroblasts pathology
Humans
Inflammation etiology
Inflammation metabolism
Inflammation pathology
Macrophages drug effects
Macrophages metabolism
Macrophages pathology
Mice
Mice, Inbred DBA
Pentose Phosphate Pathway
Phenotype
Arthritis, Rheumatoid physiopathology
Deoxyglucose pharmacology
Fibroblasts immunology
Glycolysis
Inflammation prevention & control
Macrophages immunology
Th17 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1420-9071
- Volume :
- 78
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Cellular and molecular life sciences : CMLS
- Publication Type :
- Academic Journal
- Accession number :
- 34705053
- Full Text :
- https://doi.org/10.1007/s00018-021-03978-5