Inflammasome Activation and Pyroptosis via a Lipid-regulated SIRT1-p53-ASC Axis in Macrophages From Male Mice and Humans

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Obesity-linked diabetes is associated with accumulation of proinflammatory macrophages into adipose tissue leading to inflammasome activation and pyroptotic secretion of interleukin (IL)-1β and IL-18. Targeting fatty acid binding protein 4 (FABP4) uncouples obesity from inflammation, attenuates characteristics of type 2 diabetes and is mechanistically linked to the cellular accumulation of monounsaturated fatty acids in macrophages. Herein we show that pharmacologic inhibition or genetic deletion of FABP4 activates silent mating type information regulation 2 homolog 1 (SIRT1) and deacetylates its downstream targets p53 and signal transducer and activator of transcription 3 (STAT3). Pharmacologic inhibition of fatty acid synthase or stearoyl-coenzyme A desaturase inhibits, whereas exogenous addition of C16:1 or C18:1 but not their saturated acyl chain counterparts, activates SIRT1 and p53/STAT3 signaling and IL-1β/IL-18 release. Expression of the p53 target gene ASC [apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (CARD)] required for assembly of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is downregulated in FABP4 null mice and macrophage cell lines leading to loss of procaspase 1 activation and pyroptosis. Concomitant with loss of ASC expression in FABP4-/- macrophages, inflammasome activation, gasdermin D processing

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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