{"id":79600,"date":"2026-10-19T05:58:09","date_gmt":"2026-10-19T03:58:09","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/10\/19\/long-term-nlrp3-gain-of-function-mutation-promotes-cardiac-dysfunction-independent-of-inflammasome-in-mice\/"},"modified":"2026-10-19T05:58:09","modified_gmt":"2026-10-19T03:58:09","slug":"long-term-nlrp3-gain-of-function-mutation-promotes-cardiac-dysfunction-independent-of-inflammasome-in-mice","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/10\/19\/long-term-nlrp3-gain-of-function-mutation-promotes-cardiac-dysfunction-independent-of-inflammasome-in-mice\/","title":{"rendered":"Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice"},"content":{"rendered":"<div>\n<p><b>J Immunol<\/b>. 2026 Oct 1;215(10):vkag257. doi: 10.1093\/jimmun\/vkag257.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>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-1\u03b2 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 \u00d7 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 \u00d7 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.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/42893808\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=2985117R&amp;ff=20261018235809&amp;v=2.20.1\">42893808<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1093\/jimmun\/vkag257\">10.1093\/jimmun\/vkag257<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>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-1\u03b2 secretion. Long-term IL-1 blockade has markedly improved patient outcomes by preventing systemic inflammation and amyloidosis. However, whether &#8230; <a title=\"Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/10\/19\/long-term-nlrp3-gain-of-function-mutation-promotes-cardiac-dysfunction-independent-of-inflammasome-in-mice\/\" aria-label=\"Read more about Long-term Nlrp3 gain-of-function mutation promotes cardiac dysfunction independent of inflammasome in mice\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[42,71],"tags":[],"class_list":["post-79600","post","type-post","status-publish","format-standard","hentry","category-publicaciones","category-the-journal-of-immunology"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/79600","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=79600"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/79600\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=79600"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=79600"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=79600"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}