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

BACKGROUND AND PURPOSE IL-1β, mainly produced by macrophages via the NLRP3 inflammasome, mediates the inflammatory crosstalk between macrophages and adipocytes. In our previous study, AEDC [(16S,20S,24R)-12β-acetoxy-16,23-epoxy-24,25-dihydroxy-3β-(β-D-xylopyranosyloxy)-9,19-cyclolanost-22(23)-ene], a cycloartane triterpenoid isolated from Actaea vaginata (Ranunculaceae), was found to possess anti-inflammatory effect on LPS-treated RAW264.7 macrophages. The current 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 were analyzed 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 In summary, AEDC attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT3-autopahgy mediated NLRP3 inflammasome inhibition, which might be a candidate for the treatment of adipose tissue inflammation-related metabolic disorders.