J Immunol. 2026 Oct 1;215(10):vkag257. doi: 10.1093/jimmun/vkag257.
ABSTRACT
Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by gain-of-function mutations in human nucleotide-binding domain, leucine-rich repeat-containing protein 3 (NLRP3), which lead to constitutive inflammasome activation and excessive IL-1β secretion. Long-term IL-1 blockade has markedly improved patient outcomes by preventing systemic inflammation and amyloidosis. However, whether chronic NLRP3 mutation exerts inflammasome-independent effects on the cardiac function remains unknown. We generated Nlrp3C257Y/WT knock-in mice as a novel CAPS model. Long-term survival, systemic inflammation, and cardiac function were assessed by biochemical, histological, and echocardiographic analyses. To determine inflammasome dependency, Nlrp3C257Y/WT mice were crossed with Asc-/- mice to generate double-mutant Nlrp3C257Y/WT × Asc-/- offspring. Nlrp3C257Y/WT mice exhibited early-onset cutaneous inflammation that gradually subsided, these mice developed marked left ventricular (LV) dilatation and mild systolic dysfunction after approximately 6 mo of age. Histological analysis revealed interstitial myocardial fibrosis in Nlrp3C257Y/WT mice. This result indicates that Nlrp3C257Y/WT mutation, which operates as a gain-of-function variant for inflammasome activation, impairs cardiac function largely driven by an inflammasome-dependent mechanism. In contrast, Nlrp3C257Y/WT × Asc-/- mice exhibited marked resolution of systemic inflammation; nevertheless, LV dilatation and reduced fractional shortening persisted. Long-term Nlrp3C257Y/WT mutation can lead to persistent cardiac dysfunction not only through inflammasome activation but also via inflammasome-independent mechanisms. Our findings reveal previously unrecognized inflammasome-independent mechanisms linking NLRP3 signaling to cardiac dysfunction. This study expands knowledge of the pathophysiological spectrum of CAPS and highlights inflammasome-independent NLRP3 signaling as a potential therapeutic target to prevent chronic cardiac complications in patients with CAPS and NLRP3-associated disorders.
PMID:42893808 | DOI:10.1093/jimmun/vkag257