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Inhibition of PDE4 by apremilast attenuates skin fibrosis through directly suppressing activation of M1 and T cells

Abstract

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients.

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Fig. 1: Inhibition of PDE4 attenuated the pathological manifestations in BLM-induced murine skin fibrosis.
Fig. 2: Inhibition of PDE4 suppressed the expression of pro-fibrotic factors in BLM-induced murine skin fibrosis.
Fig. 3: Inhibition of PDE4 regulated the expression and downstream signaling transduction of PDE4.
Fig. 4: Inhibition of PDE4 decreased the infiltration of inflammatory monocytes and the polarization of M1.
Fig. 5: Inhibition of PDE4 inhibited the infiltration and activation of T cells.
Fig. 6: Inhibition of PDE4 suppressed the inflammatory responses in BLM-induced murine skin fibrosis.
Fig. 7: The schematic diagram of inhibition of PDE4 in attenuating skin fibrosis through directly suppressing activation of M1 and T cells.

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Acknowledgements

This work was granted by the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program,” China (2018ZX09711002–006–011), CAS Key Laboratory of Receptor Research (SIMM1904YKF-01), Science & Technology Commission of Shanghai Municipality, China (No. 18431907100), and “Personalized Medicines-Molecular Signature-based Drug Discovery and Development,” Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020231).

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QKL, HML, and WT designed research and contributed to the conception. QKL, CF, CGX, BW, HML, CLF, XQY, and HL performed research. QKL and HL analyzed data. QKL, HL, and WT wrote the paper. All the authors contributed to the collection and interpretation of data and approved the final draft.

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Correspondence to Heng Li or Wei Tang.

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The authors declare no competing interests.

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Lu, Qk., Fan, C., Xiang, Cg. et al. Inhibition of PDE4 by apremilast attenuates skin fibrosis through directly suppressing activation of M1 and T cells. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00656-x

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Keywords

  • PDE4
  • apremilast
  • skin fibrosis
  • macrophages

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