Small molecule‐driven SIRT3‐autophagy‐mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes

Tian Zhang; Zhujun Fang; Ke‐Gang Linghu; Jingxin Liu; Lishe Gan; Ligen Lin

doi:10.1111/bph.15215

journal article Aug 20, 2020

Small molecule‐driven SIRT3‐autophagy‐mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes

Tian Zhang

Zhujun Fang Ke‐Gang Linghu Jingxin Liu

Lishe Gan Ligen Lin

British Journal of Pharmacology Vol. 177 No. 20 pp. 4645-4665 · Wiley

View at Publisher Save 10.1111/bph.15215

Abstract

Background and PurposeIL‐1β produced by macrophages via the NOD‐, LRR‐ and pyrin domain‐containing 3 (NLRP3) inflammasome, mediates the inflammatory crosstalk between macrophages and adipocytes. In our previous study, (16S,20S,24R)‐12β‐acetoxy‐16,23‐epoxy‐24,25‐dihydroxy‐3β‐(β‐D‐xylopyranosyloxy)‐9,19‐cyclolanost‐22(23)‐ene (AEDC), a cycloartane triterpenoid isolated from Actaea vaginata (Ranunculaceae), was found to possess anti‐inflammatory effect on LPS‐treated RAW264.7 macrophages. This study was designed to investigate whether AEDC modulates macrophage–adipocyte crosstalk to alleviate adipose tissue inflammation.Experimental ApproachThe anti‐inflammatory effect of AEDC was evaluated on LPS plus ATP‐induced THP‐1 macrophages and C57BL/6J mice. The expression of autophagy‐related and NLRP3 inflammasome complex proteins was analysed by western blots, immunofluorescence staining and co‐immunoprecipitation. The pro‐inflammatory cytokines levels were determined by ELISA kits. The adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining.Key ResultsAEDC (5 and 10 μM) activated autophagy, which in turn suppressed the NLRP3 inflammasome activation and IL‐1β secretion in THP‐1 macrophages. AEDC increased the expression of SIRT3 deacetylase and enhanced its deacetylating activity to reverse mitochondrial dysfunction and activate AMP‐activated protein kinase, which together induced autophagy. Moreover, AEDC (10 μM) attenuated macrophage conditioned medium‐induced inflammatory responses in adipocytes and blocked THP‐1 macrophages migration towards 3T3‐L1 adipocytes. In inflammation mice, AEDC (5 and 20 mg·kg−1) treatment reduced the levels of pro‐inflammatory cytokines in serum and epididymal adipose tissue and reduced macrophage infiltration to alleviate adipose tissue inflammation.Conclusion and ImplicationsAEDC attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT3‐autophagy‐mediated NLRP3 inflammasome inhibition, which might used for the treatment of adipose tissue inflammation‐related metabolic disorders.

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Details

Published: Aug 20, 2020
Vol/Issue: 177(20)
Pages: 4645-4665
License: View

Authors

T

Tian Zhang

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau, Avenida da Universidade Macau China

Z

Zhujun Fang

College of Pharmaceutical Sciences Zhejiang University Hangzhou China

K

Ke‐Gang Linghu

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau, Avenida da Universidade Macau China

J

Jingxin Liu

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau, Avenida da Universidade Macau China

L

Lishe Gan

School of Biotechnology and Health Sciences Wuyi University Jiangmen China; College of Pharmaceutical Sciences Zhejiang University Hangzhou China

L

Ligen Lin

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences University of Macau, Avenida da Universidade Macau China

Funding

National Natural Science Foundation of China Award: 81872754

Universidade de Macau Award: MYRG2018‐00037‐ICMS

Cite This Article

Tian Zhang, Zhujun Fang, Ke‐Gang Linghu, et al. (2020). Small molecule‐driven SIRT3‐autophagy‐mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes. British Journal of Pharmacology, 177(20), 4645-4665. https://doi.org/10.1111/bph.15215

Small molecule‐driven SIRT3‐autophagy‐mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes

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