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

Adipocytes Animals Autophagy Inflammasomes Interleukin-1beta Macrophages Mice Mice, Inbred C57BL Mice, Inbred NOD NLR Family, Pyrin Domain-Containing 3 Protein Sirtuin 3
IL-1β, macrophages NLRP3 inflammasome adipocytes adipose tissue inflammation autophagy cycloartane triterpenoid

Journal

British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536

Informations de publication

Date de publication:
10 2020
Historique:
received: 19 12 2019
revised: 03 06 2020
accepted: 15 07 2020
pubmed: 30 7 2020
medline: 22 6 2021
entrez: 30 7 2020
Statut: ppublish

Résumé

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. 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. 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 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.

Sections du résumé

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
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.

Identifiants

DOI: 10.1111/bph.15215 PMID: 32726464 PMC: PMC7520450
pubmed: 32726464
doi: 10.1111/bph.15215
pmc: PMC7520450
doi:

Substances chimiques

Inflammasomes 0
Interleukin-1beta 0
NLR Family, Pyrin Domain-Containing 3 Protein 0
Nlrp3 protein, mouse 0
Sirt3 protein, mouse 0
Sirtuin 3 EC 3.5.1.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

4645-4665

Subventions

Organisme : Zhejiang Provincial Natural Science Foundation of China
ID : LR17H300001
Organisme : University of Macau
ID : MYRG2018-00037-ICMS
Organisme : University of Macau
ID : MYRG2017-00109-ICMS
Organisme : Science and Technology Development Fund, Macau SAR
ID : FDCT 0031/2019/A1
Organisme : National Natural Science Foundation of China
ID : 81872754
Organisme : National Natural Science Foundation of China
ID : 81872756

Informations de copyright

© 2020 The British Pharmacological Society.

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Auteurs

Tian Zhang (T)

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

Zhujun Fang (Z)

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Ke-Gang Linghu (KG)

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

Jingxin Liu (J)

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

Lishe Gan (L)

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

Ligen Lin (L)

State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Macau, China.
ORCID: 0000-0002-6799-5327

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Adipocytes › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Autophagie › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Structures macromoléculaires › Complexes multiprotéiques › Inflammasomes › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Monokines › Interleukine-1 › Interleukine-1 bêta › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée NOD › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Protéines NLR › Protéine-3 de la famille des NLR contenant un domaine pyrine › Small molecule-driven SIRT3-autophagy-mediated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines mitochondriales › Sirtuine-3 › Small molecule-driven SIRT3-autophagy-mediated...