Targeting macrophage TFEB-14-3-3 epsilon Interface by naringenin inhibits abdominal aortic aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

Naringenin facilitates M2 macrophage polarization after myocardial ischemia–reperfusion by promoting nuclear translocation of transcription factor EB and inhibiting the NLRP3 inflammasome pathway

“…NAR can promote intracellular degradation of pro‐inflammatory cytokines in macrophages through lysosome‐ and TFEB‐dependent mechanisms 37 . TFEB may play a contributory role in macrophage M2 polarization 58 . TFEB activation attenuates NLRP3‐induced inflammation in severe asthma 59 .…”

“…The result proved the promotional action of NAR on TFEB nuclear translocation, consistent with a recent report that NAR directly binds to the 14-3-3-epsilon and block the TFEB-14-3-3-3-epsilon interaction to promote TFEB nuclear translocation and activation, thereby exerting preventive and therapeutic effects on abdominal aortic aneurysm. 58 NAR can promote intracellular degradation of pro-inflammatory cytokines in macrophages through lysosome-and TFEB-dependent mechanisms. 37 TFEB may play a contributory role in macrophage M2 polarization.…”

“…37 TFEB may play a contributory role in macrophage M2 polarization. 58 TFEB activation attenuates NLRP3-induced inflammation in severe asthma. 59 After silencing TFEB, M1 macrophages were increased while M2 macrophages were decreased, together with elevated levels system.…”

Naringenin restores colistin activation against colistin-resistant gram-negative bacteria in vitro and in vivo

“…Each mouse was injected with 100 μl of bacterial suspension (1.5 × 10 7 CFU/ml) in the posterior thigh muscle index. After 2 h of bacterial inoculation, colistin 7.5 mg/kg was injected intraperitoneally every 24 h, alone or in combination with NG (50 mg/kg every 24 h) ( Jia et al, 2022 ). Mice were euthanized after 24 h of treatment.…”

Worm Generator: A System for High-Throughput in Vivo Screening

“…All of these compounds have previously been reported to have antioxidant properties in vitro / in vivo. − Notably, some structurally similar compounds were successfully differentiated by their identified fingerprints. For example, matrine, allomatrine, and oxymatrine were separated into groups 7, 5, and 2, respectively (Figure d).…”