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Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes
Zhang,Tian1; Fang,Zhujun3; Linghu,Ke Gang1; Liu,Jingxin1; Gan,Lishe2,3; Lin,Ligen1
2020-10
Source PublicationBritish Journal of Pharmacology
ISSN0007-1188
Volume177Issue:20Pages:4645-4665
Abstract

Background and Purpose: IL-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 Approach: The 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 Results: AEDC (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) 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 Implications: AEDC 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.

KeywordAdipocytes Adipose Tissue Inflammation Autophagy Cycloartane Triterpenoid Il-1β, Macrophages Macrophages Nlrp3 Inflammasome
DOI10.1111/bph.15215
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000561020900001
Scopus ID2-s2.0-85089600506
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Cited Times [WOS]:21   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorGan,Lishe; Lin,Ligen
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine,Institute of Chinese Medical Sciences,University of Macau,Avenida da Universidade,Macao
2.School of Biotechnology and Health Sciences,Wuyi University,Jiangmen,China
3.College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,China
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Zhang,Tian,Fang,Zhujun,Linghu,Ke Gang,et al. Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes[J]. British Journal of Pharmacology,2020,177(20):4645-4665.
APA Zhang,Tian,Fang,Zhujun,Linghu,Ke Gang,Liu,Jingxin,Gan,Lishe,&Lin,Ligen.(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.
MLA Zhang,Tian,et al."Small molecule-driven SIRT3-autophagy-mediated NLRP3 inflammasome inhibition ameliorates inflammatory crosstalk between macrophages and adipocytes".British Journal of Pharmacology 177.20(2020):4645-4665.
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