title: Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis.
abstract: TNF ligand superfamily member 12, also known as TNF-related weak inducer of apoptosis (TWEAK), acts through its receptor, fibroblast growth factor-inducible 14 (Fn14), to mediate several key pathologic processes involved in tissue injury relating to lupus nephritis. To explore the potential for renal protection in lupus nephritis by targeting this pathway, we introduced the Fn14 null allele into the MRL-lpr/lpr lupus mouse strain. At 26-38 weeks of age, female Fn14-knockout MRL-lpr/lpr mice had significantly lower levels of proteinuria compared with female wild-type MRL-lpr/lpr mice. Furthermore, Fn14-knockout mice had significantly improved renal histopathology accompanied by attenuated glomerular and tubulointerstitial inflammation. There was a significant reduction in glomerular Ig deposition in Fn14-knockout mice, despite no detectable differences in either serum levels of antibodies or splenic immune cell subsets. Notably, we found that the Fn14-knockout mice displayed substantial preservation of podocytes in glomeruli and that TWEAK signaling directly damaged barrier function and increased filtration through podocyte and glomerular endothelial cell monolayers. Our results show that deficiency of the Fn14 receptor significantly improves renal disease in a spontaneous lupus nephritis model through prevention of the direct injurious effects of TWEAK on the filtration barrier and/or modulation of cytokine production by resident kidney cells. Thus, blocking the TWEAK/Fn14 axis may be a novel therapeutic intervention in immune-mediated proliferative GN.
authors.affiliation: Department of Microbiology and Immunology and Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Yumin
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Pathology, Columbia-Presbyterian Medical Center, New York, New York;
authors.forename: Leal C
authors.initials: LC
authors.lastname: Herlitz
authors.affiliation: Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Simona
authors.initials: S
authors.lastname: Gindea
authors.affiliation: Department of Microbiology and Immunology and.
authors.forename: Jing
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Microbiology and Immunology and Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York;
authors.forename: Rahul D
authors.initials: RD
authors.lastname: Pawar
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
authors.forename: Alexander
authors.initials: A
authors.lastname: Misharin
authors.affiliation: Division of Rheumatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, Massachusetts; and.
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, Massachusetts; and.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Tumor Immunology, Jounce Therapeutics, Cambridge, Massachusetts.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.affiliation: Department of Immunology, Biogen Idec, Cambridge, Massachusetts; and.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Department of Microbiology and Immunology and Division of Rheumatology, Albert Einstein College of Medicine, Bronx, New York; chaim.putterman@einstein.yu.edu.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D000074049:Cytokine TWEAK; D005260:Female; D005346:Fibroblast Growth Factors / Q000172:deficiency*; D060730:Glomerular Filtration Barrier / Q000378:metabolism*; D007074:Immunoglobulin G / Q000378:metabolism; D008181:Lupus Nephritis / Q000209:etiology*; D018345:Mice, Knockout; D011507:Proteinuria / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D000074049:Cytokine TWEAK; D007074:Immunoglobulin G; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; C112971:fibroblast growth factor 14; D005346:Fibroblast Growth Factors
keywords: clinical immunology; cytokines; lupus nephritis