{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:03:27Z","timestamp":1784581407547,"version":"3.55.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Kawasaki disease (KD) is the leading cause of acquired heart disease in children. While circulating neutrophils are increased and activated during acute KD, it is unclear whether neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of KD. Peptidylarginine deiminase 4 (PAD4), an enzyme involved in protein citrullination and essential for NETs formation, is implicated in the pathogenesis of various diseases. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced mouse model of KD vasculitis to determine the contribution of PAD4 in KD vasculitis. We found that the pan-PADs inhibitor, Cl-amidine, significantly reduced LCWE-induced cardiovascular lesions, but neutrophil-specific Padi4 KO mice did not impact the development of KD vasculitis. While in vitro treatment of macrophages, which highly express Padi4, with Cl-amidine inhibited IL-1\u03b2 secretion, macrophage-specific Padi4 KO mice did not reduce the lesions. Padi4\u2212\/\u2212 mice also developed KD vasculitis, AFM30a, a PAD2 inhibitor, significantly reduced KD vasculitis in Padi4\u2212\/\u2212 mice, indicating a compensatory role of PAD2 in PAD4 deficiency. We also identified several citrullinated proteins in macrophages with constitutively active NLRP3 inflammasome that were inhibited by Cl-amidine treatment, suggesting that protein citrullination participates in NLRP3 inflammasome activation. These data indicate a dispensable role for PAD4-dependent NETs formation, and a redundant role of PAD2 and PAD4 in this murine KD vasculitis. The cardioprotective effects of Cl-amidine to reduce the severity of murine KD vasculitis are not limited to PAD4 inhibition and may include decreased citrullination in the inflammasome pathway.<\/jats:p>","DOI":"10.1093\/cei\/uxae080","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T20:08:41Z","timestamp":1725912521000},"page":"314-328","source":"Crossref","is-referenced-by-count":6,"title":["Redundant role of PAD2 and PAD4 in the development of cardiovascular lesions in a mouse model of Kawasaki disease vasculitis"],"prefix":"10.1093","volume":"218","author":[{"given":"Talita P","family":"Domiciano","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youngho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thacyana T","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiko","family":"Wakita","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Martinon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prasant K","family":"Jena","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Fert-Bober","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Borges","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R","family":"Crother","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbie","family":"Moreira","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E","family":"Van Eyk","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magali","family":"Noval Rivas","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Arditi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8213-5686","authenticated-orcid":false,"given":"Kenichi","family":"Shimada","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Guerin Children\u2019s at Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]},{"name":"Infectious and Immunologic Diseases Research Center (IIDRC) and Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, CA ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"key":"2024111301165660200_CIT0001","doi-asserted-by":"crossref","first-page":"e927","DOI":"10.1161\/CIR.0000000000000484","article-title":"Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association","volume":"135","author":"McCrindle","year":"2017","journal-title":"Circulation"},{"key":"2024111301165660200_CIT0002","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41584-020-0426-0","article-title":"Kawasaki disease: pathophysiology and insights from mouse models","volume":"16","author":"Noval Rivas","year":"2020","journal-title":"Nat Rev 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Res"},{"key":"2024111301165660200_CIT0006","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/art.41481","article-title":"Phase II open label study of anakinra in intravenous immunoglobulin-resistant Kawasaki disease","volume":"73","author":"Kon\u00e9-Paut","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"2024111301165660200_CIT0007","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jpeds.2021.12.035","article-title":"Anakinra treatment in patients with acute Kawasaki disease with coronary artery aneurysms: a phase I\/IIa trial","volume":"243","author":"Yang","year":"2022","journal-title":"J Pediatr"},{"key":"2024111301165660200_CIT0008","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1161\/ATVBAHA.115.307072","article-title":"Role of Interleukin-1 signaling in a mouse model of Kawasaki disease-associated abdominal aortic aneurysm","volume":"36","author":"Wakita","year":"2016","journal-title":"Arterioscler Thromb Vasc 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neutrophils","volume":"70","author":"Asaga","year":"2001","journal-title":"J Leukoc Biol"},{"key":"2024111301165660200_CIT0021","doi-asserted-by":"crossref","first-page":"e124729","DOI":"10.1172\/jci.insight.124729","article-title":"Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus","volume":"3","author":"Liu","year":"2018","journal-title":"JCI Insight"},{"key":"2024111301165660200_CIT0022","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1084\/jem.20100239","article-title":"PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps","volume":"207","author":"Li","year":"2010","journal-title":"J Exp Med"},{"key":"2024111301165660200_CIT0023","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1136\/ard.2003.012211","article-title":"Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and 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