{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:33:54Z","timestamp":1772559234186,"version":"3.50.1"},"posted":{"date-parts":[[2024,9,6]]},"group-title":"Molecular Biology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 AG060195"],"award-info":[{"award-number":["R01 AG060195"]}]},{"name":"NIH","award":["AI15586901"],"award-info":[{"award-number":["AI15586901"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Inflammation has an essential role in healing. However, over-active inflammation disrupts normal cellular functions and can be life-threatening when not resolved. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, a component of the innate immune system, is an intracellular multiprotein complex that senses stress-associated signals, and, for this reason is a promising therapeutic target for treating unresolved, pathogenic inflammation. Alternative splicing of\n                  <jats:italic>NLRP3<\/jats:italic>\n                  RNA has been suggested as a regulatory mechanism for inflammasome activation, as some spliced isoforms encode NLRP3 proteins with compromised function. Here, we take advantage of this natural regulatory mechanism and devise a way to control pathogenic inflammation using splice-switching antisense oligonucleotides (ASOs). To identify and induce NLRP3 isoforms lacking inflammatory activity, we tested a series of ASOs, each targeting a different exon, to determine the most effective strategy for down-regulating NLRP3. We identify several ASOs that modulate\n                  <jats:italic>NLRP3<\/jats:italic>\n                  splicing, reduce NLRP3 protein, and decrease inflammasome signaling in vitro. The most effective ASO suppresses systemic inflammation in vivo in mouse models of acute inflammation and cryopyrin-associated periodic syndrome (CAPS). Overall, these results demonstrate how ASOs can be used to systematically engineer proteins with modified functions and treat pathological inflammation in mice by reducing functional NLRP3.\n                <\/jats:p>","DOI":"10.1101\/2024.09.06.611206","type":"posted-content","created":{"date-parts":[[2024,9,7]],"date-time":"2024-09-07T01:25:48Z","timestamp":1725672348000},"source":"Crossref","is-referenced-by-count":2,"title":["Modulating NLRP3 splicing with antisense oligonucleotides to control pathological inflammation"],"prefix":"10.64898","author":[{"given":"Roni","family":"Klein","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janset","family":"Onyuru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Centa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estela M.","family":"Viera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fox J.","family":"Duelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher D.","family":"Putnam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hal M.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4253-9261","authenticated-orcid":false,"given":"Michelle L.","family":"Hastings","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025050500001009000_2024.09.06.611206v3.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.04.025"},{"key":"2025050500001009000_2024.09.06.611206v3.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00849-x"},{"key":"2025050500001009000_2024.09.06.611206v3.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2022.04.003"},{"key":"2025050500001009000_2024.09.06.611206v3.4","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-061020-053734"},{"key":"2025050500001009000_2024.09.06.611206v3.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature04516"},{"key":"2025050500001009000_2024.09.06.611206v3.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature08938"},{"key":"2025050500001009000_2024.09.06.611206v3.7","doi-asserted-by":"publisher","DOI":"10.1038\/nature11729"},{"key":"2025050500001009000_2024.09.06.611206v3.8","doi-asserted-by":"crossref","unstructured":"Trudler D , Nazor KL , Eisele YS , Grabauskas T , Dolatabadi N , Parker J , et al. 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