Abstract Macrophage polarization determines the production of pro‐ or anti‐inflammatory cytokines in response to various bacterial and virus infections. Here, we report that pro‐inflammatory macrophage polarization induced by lipopolysaccharide (LPS) skews the TRIM21‐SIRT5 interplay toward TRIM21 activation and SIRT5 degradation, resulting in an enhancement of interleukin (IL)‐1β production in vitro and in vivo. Mechanistically, LPS challenge enhances the interaction between TRIM21 and SIRT5 to promote SIRT5 ubiquitination and degradation, while reducing the binding of SIRT5 to HAUSP, a deubiquitinating enzyme that stabilizes SIRT5. In a feedback loop, SIRT5 degradation sustains the acetylation of TRIM21 at Lys351, thereby increasing its E3 ligase activity in LPS‐activated macrophages. Thus, we identify a functional balance between TRIM21 and SIRT5 that is tilted toward SIRT5 suppression in response to LPS stimulation, thereby enhancing IL‐1β production during inflammation.
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