Macrophage SBK2 suppresses inflammation and atherosclerosis by NLRP3 phosphorylation

BACKGROUND AND AIMS: Atherosclerosis (AS), a chronic inflammatory disorder, persists as the predominant contributor to global cardiovascular morbidity and mortality. Macrophage-mediated inflammatory response plays a pivotal role in atherosclerotic lesion progression. This study investigates the functional significance and therapeutic potential of macrophage SH3 domain-binding kinase 2 (SBK2) in AS pathogenesis, with particular emphasis on its translational relevance. METHODS: Single-cell sequencing data of atherosclerotic plaques in mice fed with high-fat diet for different time periods were analysed. SBK2 expression levels were quantified in both human atherosclerotic lesions and murine arterial tissues. This study evaluated the impacts of SBK2 whole-body knockout, macrophage-specific knockout, and overexpression on murine AS progression. The molecular mechanisms were systematically investigated through integrated approaches including single-cell sequencing, co-immunoprecipitation assays, in vitro kinase activity assays, and mass spectrometry analysis. High-throughput screening of a small-molecule compound library identified potent SBK2 agonists. RESULTS: SBK2 expression was elevated in macrophages within advanced murine and human atherosclerotic plaques. Despite this upregulation, genetic ablation or macrophage-specific SBK2 deficiency exacerbated plaque formation and inflammatory responses, whereas macrophage-targeted SBK2 overexpression attenuated disease progression. This indicates that SBK2 induction represents a compensatory protective response within the atherosclerotic microenvironment. Mechanistic studies revealed that SBK2 phosphorylates NLRP3 at Ser161, triggering Tollip-dependent autophagic degradation of the inflammasome component and subsequent inflammasome inactivation. Pharmacological activation of SBK2 using rebaudioside N (RN) effectively suppressed NLRP3-mediated IL-1β/IL-18 secretion, reduced inflammatory responses, and diminished atherosclerotic burden. Notably, RN's therapeutic effects were completely abolished in SBK2-deficient models, validating its target specificity. CONCLUSIONS: Macrophage SBK2 serves as an endogenous safeguard factor that suppresses atherosclerosis by phosphorylating NLRP3 to enable its selective autophagic degradation. SBK2 is identified as the sole known protein kinase capable of mediating the selective clearance of this inflammasome. Targeting the SBK2-NLRP3 axis with RN offers a precise therapeutic strategy to mitigate inflammatory cardiovascular risk. This study identifies SBK2 as a novel therapeutic target and highlights kinase-driven inflammasome resolution as a paradigm for AS management.