Long-term Nlrp3 C257Y/WT gain-of-function mutation in mice caused left ventricular dilatation, mild systolic dysfunction, and interstitial myocardial fibrosis after about 6 months of age, and these cardiac abnormalities persisted when systemic inflammation was resolved by Asc deletion, indicating inflammasome-independent mechanisms of NLRP3-associated cardiac dysfunction.
Nlrp3 C257Y/WT knock-in mice were generated as a novel CAPS model and showed early-onset cutaneous inflammation that gradually subsided.
Nlrp3 C257Y/WT mice developed marked left ventricular (LV) dilatation and mild systolic dysfunction after approximately 6 months of age.
Nlrp3 C257Y/WT mice showed interstitial myocardial fibrosis on histological analysis.
Deleting Asc in Nlrp3 C257Y/WT mice markedly resolved systemic inflammation, but LV dilatation and reduced fractional shortening persisted.
Chronic Nlrp3 mutation can lead to persistent cardiac dysfunction via both inflammasome activation and inflammasome-independent mechanisms.
The authors propose that inflammasome-independent NLRP3 signaling is a potential therapeutic target for chronic cardiac complications in CAPS and NLRP3-associated disorders.
Cryopyrin-associated periodic syndrome (CAPS) is an inherited inflammatory disease caused by mutations that make a protein called NLRP3 overactive, leading to excess inflammation driven by a molecule called IL-1β. Drugs that block IL-1 have greatly improved outcomes for patients, but it was unknown whether the mutated NLRP3 could harm the heart over the long term through routes other than this inflammation pathway. Researchers created mice carrying a CAPS-causing Nlrp3 mutation. These mice had skin inflammation early in life that faded, but after about 6 months of age they developed an enlarged left heart chamber, mildly reduced pumping function, and scarring (fibrosis) in the heart muscle. When the researchers also removed ASC, a key part of the inflammasome machinery, body-wide inflammation largely resolved, yet the enlarged heart chamber and reduced pumping function persisted. This research suggests that the mutated NLRP3 can damage the heart partly through the classic inflammasome pathway and partly through mechanisms independent of it. This may mean that treatments targeting only inflammasome-driven inflammation might not fully prevent long-term heart problems in CAPS. These findings come from mice, so further work would be needed to know whether the same applies to patients.
Kurata M, Takahashi K, Kaneko N, Kameda K, Nakamura T, Hosokawa S, et al.. (2026). Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice.. Journal of immunology (Baltimore, Md. : 1950). https://doi.org/10.1093/jimmun/vkag257