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

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−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 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.

Downregulating lncRNA PRNCR1 ameliorates LPS‐induced pulmonary vascular endothelial cell injury by modulating miR‐330‐5p/TLR4 axis

“…During inflammatory processes, the NLRP3 could be activated by IL‐1β, which is generated by immune cells, such as macrophages and microglia. [ 28,29 ] After being activated, NLRP3 inflammasome binds to an apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC), and then ASC activates its downstream caspase‐1 through caspase activation and recruitment domain (CARD) interaction. Caspase‐1 cleaves the precursors of IL‐1 β and IL‐18, promotes their maturation, and induces amplification of inflammatory response cascade and programmed cell death.…”

The NLRP3 inflammasome: an emerging therapeutic target for chronic pain

“…The NLRP3 inflammasome consists of NLRP3, ASC adaptors, and caspase-1 enzymes [10,11]. The NLRP3 inflammasome is present primarily in immune and inflammatory cells, including mast cells, neutrophils, and macrophages, following activation by inflammatory stimuli [12][13][14]. Recent studies also identified NLRP3 inflammasome in neurons of the sensory nerve system [15].…”

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“…AEDC is a cycloartane triterpenoid isolated from the whole plant of Amanita vaginata ( Fang et al, 2019 ). Zhang et al (2020) found that AEDC suppressed LPS plus ATP-induced NLRP3 inflammasome activation and IL-1β secretion in THP-1 macrophages. Moreover, LPS plus ATP notably decreased the protein levels of Atg5, Atg7, beclin 1 and the ratio of LC3-II/LC3-I and increased the level of p62, while AEDC had opposite effects, indicating that AEDC restored autophagy impaired by LPS plus ATP.…”