title: Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations inFaslprMice.
abstract: Cysteinyl cathepsin K (CatK) is expressed in osteoclasts to mediate bone resorption, but is also inducible under inflammatory conditions.Faslprmice on a C57BL/6 background develop spontaneous systemic lupus erythematosus-like manifestations. Although normal mouse kidneys expressed negligible CatK, those fromFaslprmice showed elevated CatK expression in the glomeruli and tubulointerstitial space.Faslprmice also showed elevated serum CatK levels. CatK deficiency inFaslprmice reduced all tested kidney pathologies, including glomerulus and tubulointerstitial scores, glomerulus complement C3 and IgG deposition, chemokine expression and macrophage infiltration, and serum autoantibodies. CatK contributed toFaslprmouse autoimmunity and pathology in part by its activity in TLR-7 proteolytic processing and consequent regulatory T (Treg) cell biology. Elevated TLR7 expression and proteolytic processing inFaslprmouse kidneys and Tregs showed significantly reduced levels in CatK-deficient mice, leading to increased spleen and kidney Treg content. Purified CD4+CD25highFoxp3+Tregs from CatK-deficient mice doubled their immunosuppressive activity against T effector cells, compared with those from CatK-sufficient mice. InFaslprmice, repopulation of purified Tregs from CatK-sufficient mice reduced spleen sizes, autoantibody titers, and glomerulus C3 and IgG deposition, and increased splenic and kidney Treg contents. Tregs from CatK-deficient mice had significantly more potency than CatK-sufficient Tregs in reducing spleen sizes, serum autoantibody titers, and glomerulus C3 deposition, and in increasing splenic and kidney Treg content. This study established a possible role of CatK in TLR7 proteolytic activation, Treg immunosuppressive activity, and lupus autoimmunity and pathology.
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.|Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.|Research Institute of Nephrology, Nanjing University School of Medicine, Nanjing 210002, China.
authors.forename: Huimei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Biology, School of Life Science, Huzhou Teachers College, Huzhou, Zhejiang 313000, China.
authors.forename: Li
authors.identifier: 0000-0002-7649-8904
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nephrology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China; gshi@rics.bwh.harvard.edu yuxq@mail.sysu.edu.cn.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Galina K
authors.identifier: 0000-0002-1421-9455
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: Department of Rheumatology, Nan Fang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Isaac E
authors.identifier: 0000-0002-4224-5060
authors.initials: IE
authors.lastname: Stillman
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Bruce
authors.identifier: 0000-0001-8527-5027
authors.initials: B
authors.lastname: Gelb
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Peter
authors.identifier: 0000-0002-1502-502X
authors.initials: P
authors.lastname: Libby
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: George C
authors.identifier: 0000-0001-9589-2360
authors.initials: GC
authors.lastname: Tsokos
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; gshi@rics.bwh.harvard.edu yuxq@mail.sysu.edu.cn.
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D015551:Autoimmunity; D056657:Cathepsin K / Q000097:blood / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D003176:Complement C3 / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000503:physiopathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology*; D008181:Lupus Nephritis / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D013154:Spleen / Q000276:immunology / Q000503:physiopathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: D003176:Complement C3; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D019014:fas Receptor; D056657:Cathepsin K