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Temporal expression patterns of distinct cytokines and M1/M2 macrophage polarization regulate rheumatoid arthritis progression

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial joints and often associated with chronic pain. Chronic joint inflammation is attributed to severe proliferation of synoviocytes and resident macrophages and infiltration of immune cells. These cells secrete pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and IL-17 to overcome actions of anti-inflammatory cytokines, thereby maintaining chronic inflammation and pain. The imbalance between pro-inflammatory cytokines (produced by M1 macrophages) and anti-inflammatory cytokines (produced by M2 macrophages) is a feature of RA progression, but the switch time of M1/M2 polarization and which receptor regulates the switch remain unsolved. Here we used an established RA mouse model to demonstrate that TNF-α expression was responsible for the initial acute stage of inflammation and pain (1–4 weeks), IL-17 expression the transition stage (4–12 weeks), and IL-6 expression the later maintenance stage (> 12 weeks). The switch time of M1/M2 polarization occurred at 4–8 weeks. We also identified a potential compound, anthra[2,1-c][1,2,5] thiadiazole-6,11-dione (NSC745885), that specifically inhibited T-cell death-associated gene 8 (TDAG8) function and expression. NSC745885 decreased joint inflammation and destruction and attenuated pain by reducing cytokine production and regulating the M1/M2 polarization switch. TDAG8 may participate in regulating the M1/M2 polarization and temporal expression of distinct cytokines to control RA progression.

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Acknowledgements

We thank the Taiwan Mouse Clinic (MOST 107-2319-B-001-002), which is funded by the National Research Program for Biopharmaceuticals (NRPB) at the Ministry of Science and Technology (MOST) of Taiwan, for technical support in H&E staining.

Funding

This work was supported by the funds from the Ministry of Science and Technology, Taiwan (Grant No. MOST 106-2320-B-008-004-MY3).

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CCK participated in the animal model, data analysis and manuscript writing. SPD contributed to in vivo and in vitro tests of compounds, data analysis and manuscript writing. HC participated in animal experiments, immunostaining, and cytokine analysis, and manuscript writing. HSH contributed to the compound design, synthesis, and testing. WHS initiated the project, conceived the study, and participated in experimental design, coordination and data interpretation, and manuscript writing.

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Correspondence to Wei-Hsin Sun.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Kung, CC., Dai, SP., Chiang, H. et al. Temporal expression patterns of distinct cytokines and M1/M2 macrophage polarization regulate rheumatoid arthritis progression. Mol Biol Rep 47, 3423–3437 (2020). https://doi.org/10.1007/s11033-020-05422-6

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Keywords

  • TDAG8
  • Rheumatoid arthritis
  • Chronic pain
  • M1 macrophages
  • M2 macrophages
  • TNF-α
  • IL-6
  • IL-17