title: TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus.
abstract: TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, is a prominent inducer of proinflammatory cytokines in vitro and in vivo. We previously found that kidney cells display the TWEAK receptor Fn14, and that TWEAK stimulation of mesangial cells and podocytes induces a potent proinflammatory response. Several of the cytokines up-regulated in the kidney in response to TWEAK are instrumental in Lupus nephritis; we therefore hypothesized that TWEAK/Fn14 interactions may be important in the cascade(s) leading to renal damage in systemic Lupus erythematosus. In this study, we analyzed the effects of Fn14 deficiency in the chronic graft-vs-host model of SLE, and the benefits of treatment with an anti-TWEAK mAb in this mouse model. We found that anti-nuclear Ab titers were no different between C57BL/6 Fn14 wild-type and deficient mice injected with alloreactive bm12 splenocytes. However, kidney disease was significantly less severe in Fn14 knockout mice. Furthermore, kidney IgG deposition, IL-6, MCP-1, RANTES, and IP-10, as well as macrophage infiltration, were significantly decreased in Fn14-deficient mice with induced lupus. Similarly, mice with induced Lupus treated with an anti-TWEAK neutralizing mAb had significantly diminished kidney expression of IL-6, MCP-1, IL-10, as well as proteinuria, but similar autoantibody titers, as compared with control-treated mice. We conclude that TWEAK is an important mediator of kidney damage that acts by promoting local inflammatory events, but without impacting adaptive immunity in this experimental LN model. Thus, TWEAK blockade may be a novel therapeutic approach to reduce renal damage in SLE.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Zeguo
authors.initials: Z
authors.lastname: Zhao
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Sean
authors.initials: S
authors.lastname: Campbell
authors.forename: Noa
authors.initials: N
authors.lastname: Schwartz
authors.forename: Alberto
authors.initials: A
authors.lastname: Molano
authors.forename: Arpita
authors.initials: A
authors.lastname: Choudhury
authors.forename: Robert A
authors.initials: RA
authors.lastname: Eisenberg
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology; D018925:Chemokines / Q000187:drug effects; D002908:Chronic Disease; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology* / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011507:Proteinuria / Q000188:drug therapy; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism*; D012680:Sensitivity and Specificity; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D018925:Chemokines; D000074049:Cytokine TWEAK; D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors