Abstract
Interleukin-1β (IL-1β), a key pro-inflammatory cytokine, is majorly produced by macrophages through NOD-, LRR-, and pyrin ___domain-containing protein 3 (NLRP3) inflammasome, which has been identified as the culprit to deteriorate the inflammatory crosstalk between macrophages and adipocytes. Ainsliadimer C (AC) is a disesquiterpenoid isolated from Ainsliaea macrocephala. In the current study, we investigated the effects of AC on adipose tissue inflammation in co-culture of macrophages and adipocytes in vitro as well as in LPS-treated mice in vivo. We showed that AC (20–80 µM) dose-dependently inhibited the secretion of IL-1β from LPS plus ATP-stimulated THP-1 macrophages by inhibiting the activation of NLRP3 inflammasome. Furthermore, we found that AC treatment activated NAD+-dependent deacetylase Sirtuin 1 (SIRT1), resulting in reduced acetylation level of NLRP3. Molecular modeling analysis revealed that binding of AC to sirtuin-activating compound-binding ___domain increased the affinity of the substrate to the catalytic ___domain of SIRT1. Moreover, AC (80 µM) significantly attenuated macrophage-conditioned medium-induced inflammatory responses in 3T3-L1 adipocytes. In LPS-induced acute inflammatory mice, administration of AC (20, 60 mg·kg−1·d−1, ip) for 5 days significantly suppressed the pro-inflammatory cytokine levels in serum and epididymal white adipose tissue (eWAT), attenuated macrophage infiltration into eWAT, and mitigated adipose tissue inflammation. The beneficial effects of AC were blocked by co-administration of a selective SIRT1 inhibitor EX-527 (10 mg·kg−1·d−1). Taken together, AC suppresses NLRP3-mediated IL-1β secretion through activating SIRT1, leading to attenuated inflammation in macrophages and adipose tissue, which might be a candidate to treat obesity-associated metabolic diseases.
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Acknowledgements
This research was support by National Natural Science Foundation of China (81872754), the Science and Technology Commission of Shanghai Municipality (20430780300, 19431908100), the Science and Technology Development Fund, Macao SAR, China (File No. FDCT 0031/2019/A1), and the Research Fund of University of Macau (MYRG2018–00037-ICMS). The high-performance computing center ofUniversity of Macau is appreciated for providing computing services.
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CC, YMR, JZZ, JLC, ZLF, and TZ conducted experiments, YY and LGL designed the experiments and wrote the paper, and LGL conceived the study. All the authors approved the final proof.
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Chen, C., Ren, Ym., Zhu, Jz. et al. Ainsliadimer C, a disesquiterpenoid isolated from Ainsliaea macrocephala, ameliorates inflammatory responses in adipose tissue via Sirtuin 1-NLRP3 inflammasome axis. Acta Pharmacol Sin 43, 1780–1792 (2022). https://doi.org/10.1038/s41401-021-00797-z
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DOI: https://doi.org/10.1038/s41401-021-00797-z
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