{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:31:08Z","timestamp":1791243068368,"version":"4.1.0"},"reference-count":45,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"101","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2024,11,8]]},"abstract":"<jats:p>\n                    <jats:italic>LRRK2<\/jats:italic>\n                    polymorphisms (G2019S\/N2081D) that increase susceptibility to Parkinson\u2019s disease and Crohn\u2019s disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson\u2019s disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive\n                    <jats:italic>LRRK2<\/jats:italic>\n                    polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.adi7907","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T13:58:12Z","timestamp":1731074292000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":19,"title":["Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5889-3292","authenticated-orcid":true,"given":"Shengxiang","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5223-3822","authenticated-orcid":true,"given":"Miki","family":"Hodel","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5134-1292","authenticated-orcid":true,"given":"Xiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-0843","authenticated-orcid":true,"given":"Javier","family":"De Vicente","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9005-7750","authenticated-orcid":true,"given":"Talin","family":"Haritunians","sequence":"additional","affiliation":[{"name":"F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anketse","family":"Debebe","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount-Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0143-8445","authenticated-orcid":true,"given":"Chen-Ting","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6117-9505","authenticated-orcid":true,"given":"Changqing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1567-4154","authenticated-orcid":true,"given":"Atika","family":"Malique","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6608-7581","authenticated-orcid":true,"given":"Hoang N.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maayan","family":"Agam","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1805-1477","authenticated-orcid":true,"given":"Michael T.","family":"Maloney","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1755-5649","authenticated-orcid":true,"given":"Marisa S.","family":"Goo","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian H.","family":"Kluss","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5430-557X","authenticated-orcid":true,"given":"Richa","family":"Mishra","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1177-0897","authenticated-orcid":true,"given":"Jennifer","family":"Frein","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Foster","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6339-548X","authenticated-orcid":true,"given":"Samuel","family":"Ballentine","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8674-7257","authenticated-orcid":true,"given":"Uday","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaohong","family":"Yang","sequence":"additional","affiliation":[{"name":"F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7830-1557","authenticated-orcid":true,"given":"Emebet","family":"Mengesha","sequence":"additional","affiliation":[{"name":"F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iyshwarya","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Rutgers, State University of New Jersey, Newark, NJ 07102, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-0041","authenticated-orcid":true,"given":"Annie","family":"Arguello","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony A.","family":"Estrada","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Rutgers, State University of New Jersey, Newark, NJ 07102, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-9137","authenticated-orcid":true,"given":"Inga","family":"Peter","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount-Sinai, New York, NY 10029, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dermot P. B.","family":"McGovern","sequence":"additional","affiliation":[{"name":"F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8124-5477","authenticated-orcid":true,"given":"Anastasia G.","family":"Henry","sequence":"additional","affiliation":[{"name":"Denali Therapeutics, South San Francisco, CA 94080, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6023-3901","authenticated-orcid":true,"given":"Thaddeus S.","family":"Stappenbeck","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2800-9360","authenticated-orcid":true,"given":"Ta-Chiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature18847"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12599"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183744"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012615-044152"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.05.002"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3755"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.04.016"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2009.206466"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07416"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.05.009"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120453"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.86907"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan8162"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.004"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00660-20"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0006-9"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3233"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91917"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00193"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170558"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60478"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133264"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature24489"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.008"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2023113975"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.003"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5197"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2021.147372"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400582"},{"key":"e_1_3_2_31_2","doi-asserted-by":"crossref","unstructured":"D. Dikovskaya R. Pemberton M. Taylor A. Tasegian K. Zenevicuite E. M. Sammler A. J. M. Howden D. R. Alessi M. Swamy Regulation of leucine-rich repeat kinase 2 by inflammation and IL-4. bioRxiv 591170 [Preprint] (2024); https:\/\/doi.org\/10.1101\/2024.04.29.591170.","DOI":"10.1101\/2024.04.29.591170"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87098"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1407001111"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2021.07.004"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006962"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11866"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-022-00212-0"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2022.2039991"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28890"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.06.038"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph6020445"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202302067"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202202150"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104626"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201899430"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2021.04.004"}],"container-title":["Science Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciimmunol.adi7907","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T13:58:15Z","timestamp":1731074295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciimmunol.adi7907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,8]]},"references-count":45,"journal-issue":{"issue":"101","published-print":{"date-parts":[[2024,11,8]]}},"alternative-id":["10.1126\/sciimmunol.adi7907"],"URL":"https:\/\/doi.org\/10.1126\/sciimmunol.adi7907","relation":{},"ISSN":["2470-9468"],"issn-type":[{"value":"2470-9468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,8]]},"assertion":[{"value":"2023-05-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-26","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadi7907"}}