title: Pin1-Targeted Therapy for Systemic Lupus Erythematosus.
abstract: 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-like receptor 7 (TLR-7)/TLR-9/interleukin-1 receptor-associated kinase 1 (IRAK-1)/interferon regulatory factor 7 (IRF-7) pathway in the development and progression of SLE. Notably, the prolyl isomerase Pin1 is an essential regulator of IRAK-1 in TLR-7/TLR-9 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.
  
  
  
  Activation of Pin1 and TLR-7/TLR-9/IRAK-1/IRF-7 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-molecule Pin1 inhibitor all-trans-retinoic acid (ATRA) in immune cells and in several strains of lupus-prone mice.
  
  
  
  We found abnormal activation of Pin1 and its downstream targets IRAK-1 and IRF-7 in SLE patients. Furthermore, inhibition of Pin1 using either validated Pin1 shRNA or ATRA blocked TLR-7-induced activation of IRAK-1 and IRF-7 in SLE patient-derived immune cells. Moreover, in multiple lupus-prone animals, both Pin1 knockout and ATRA strikingly attenuated the expression of autoimmunity, including skin lesions, lymphadenopathy, splenomegaly, glomerulonephritis, proteinuria, and production of anti-double-stranded DNA antibodies and CD4-CD8- T cells, and also prolonged overall survival in MRL/lpr and B6.lpr mice.
  
  
  
  Pin1 plays a critical role in the development of SLE, and Pin1-targeted therapy offers a promising new strategy for treating SLE.
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wei
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Greg
authors.initials: G
authors.lastname: Finn
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kozono
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Morris
authors.initials: M
authors.lastname: Nechama
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhen Zhou
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, and Institute for Translational Medicine and Fujian Medical University, Fuzhou, China. klu@bidmc.harvard.edu.
authors.forename: Kun
authors.initials: K
authors.lastname: Ping Lu
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D066298:In Vitro Techniques; D050839:Interferon Regulatory Factor-7 / Q000187:drug effects* / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000187:drug effects* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000187:drug effects* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000187:drug effects* / Q000276:immunology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D050839:Interferon Regulatory Factor-7; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D034741:RNA, Small Interfering; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014212:Tretinoin; D053592:Interleukin-1 Receptor-Associated Kinases