{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:03:15Z","timestamp":1766066595609,"version":"build-2065373602"},"reference-count":56,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2016,9,28]],"date-time":"2016-09-28T00:00:00Z","timestamp":1475020800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NIH","award":["R37-AT-49954, R01-CA-167677 and R01-HL-111430"],"award-info":[{"award-number":["R37-AT-49954, R01-CA-167677 and R01-HL-111430"]}]},{"name":"Alliance for Lupus Research grant, and an Emerald Foundation Distinguished Investigator Award"},{"name":"Cure postdoctoral fellowship","award":["KG111233"],"award-info":[{"award-number":["KG111233"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,10]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic lupus erythematosus (SLE) is a debilitating autoimmune disease affecting multiple organs in the body, but therapeutic options are still very limited and often come with adverse effects. Increasing evidence has underlined an important role of the Toll\u2010like receptor 7 (TLR\u20107)\/TLR\u20109\/interleukin\u20101 receptor\u2013associated kinase 1 (IRAK\u20101)\/interferon regulatory factor 7 (IRF\u20107) pathway in the development and progression of SLE. Notably, the prolyl isomerase Pin1 is an essential regulator of IRAK\u20101 in TLR\u20107\/TLR\u20109 signaling, but its role in SLE is unknown. We undertook this study to determine whether Pin1 is activated and plays any role in the development and treatment of SLE.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Activation of Pin1 and TLR\u20107\/TLR\u20109\/IRAK\u20101\/IRF\u20107 signaling was determined in various cell types among peripheral blood mononuclear cells from healthy controls and SLE patients. The effects of Pin1 and TLR signaling on SLE development were determined using validated Pin1 short hairpin RNA (shRNA), Pin1 genetic knockout, and the small\u2010molecule Pin1 inhibitor all\u2010<jats:italic>trans<\/jats:italic>\u2010retinoic acid (ATRA) in immune cells and in several strains of lupus\u2010prone mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found abnormal activation of Pin1 and its downstream targets IRAK\u20101 and IRF\u20107 in SLE patients. Furthermore, inhibition of Pin1 using either validated Pin1 shRNA or ATRA blocked TLR\u20107\u2013induced activation of IRAK\u20101 and IRF\u20107 in SLE patient\u2013derived immune cells. Moreover, in multiple lupus\u2010prone animals, both Pin1 knockout and ATRA strikingly attenuated the expression of autoimmunity, including skin lesions, lymphadenopathy, splenomegaly, glomerulonephritis, proteinuria, and production of anti\u2013double\u2010stranded DNA antibodies and CD4\u2212CD8\u2212 T cells, and also prolonged overall survival in MRL\/<jats:italic>lpr<\/jats:italic> and B6.<jats:italic>lpr<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Pin1 plays a critical role in the development of SLE, and Pin1\u2010targeted therapy offers a promising new strategy for treating SLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39741","type":"journal-article","created":{"date-parts":[[2016,5,9]],"date-time":"2016-05-09T15:54:31Z","timestamp":1462809271000},"page":"2503-2513","source":"Crossref","is-referenced-by-count":26,"title":["Pin1\u2010Targeted Therapy for Systemic Lupus Erythematosus"],"prefix":"10.1002","volume":"68","author":[{"given":"Shuo","family":"Wei","sequence":"first","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuya","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg","family":"Finn","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shingo","family":"Kozono","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morris","family":"Nechama","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasileios C.","family":"Kyttaris","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Zhen Zhou","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George C.","family":"Tsokos","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kun","family":"Ping Lu","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, and Institute for Translational Medicine and Fujian Medical University Fuzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,9,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1100359"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-135-4-200108210-00009"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196805022781818"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24068"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.412"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2013.157"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61354-2"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30613"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5425.260"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09102"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00630.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1957"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2069"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2261"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2007.35"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2011.07.001"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5345.1957"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.283.5406.1325"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.v28.i1.30"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni0606-555"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00490-8"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1266"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1347"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603090200"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.05.088"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.109"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3839"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V72.2.567.567"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2943"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.1067"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1891"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122337"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780251101"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400928"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780350606"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.032404099"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.03.005"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C100228200"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni758"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI78087"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00610"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1966.03100040091025"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.148.5.1198"},{"key":"e_1_2_7_45_1","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.4049\/jimmunol.128.5.2322","article-title":"Ipr gene control of the anti\u2010DNA antibody response","volume":"128","author":"Pisetsky DS","year":"1982","journal-title":"J Immunol"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.10.9.8801176"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-571148-7.50008-7"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0118176"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.132657799"},{"key":"e_1_2_7_50_1","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0090-9556(25)06128-8","article-title":"Disposition of all\u2010trans\u2010retinoic acid in mice following oral doses","volume":"9","author":"Kalin JR","year":"1981","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1992.10.11.1666"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.ajkd.2009.06.012"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2004.00850.x"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2005.02654.x"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/271694"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V79.2.299.299"},{"key":"e_1_2_7_57_1","first-page":"1054","article-title":"Pharmacokinetics of oral all\u2010trans retinoic acid in patients with acute promyelocytic leukemia","volume":"5","author":"Lefebvre P","year":"1991","journal-title":"Leukemia"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39741","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.39741","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T16:13:11Z","timestamp":1759939991000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.39741"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,28]]},"references-count":56,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["10.1002\/art.39741"],"URL":"https:\/\/doi.org\/10.1002\/art.39741","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"type":"print","value":"2326-5191"},{"type":"electronic","value":"2326-5205"}],"subject":[],"published":{"date-parts":[[2016,9,28]]}}}