title: TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease.
abstract: The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-κB signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-κB signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression.
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.|Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.|Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Allie M
authors.initials: AM
authors.lastname: Roach
authors.affiliation: Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Nakagawa
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.
authors.forename: Aldo
authors.initials: A
authors.lastname: Amatucci
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.|Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.affiliation: Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom.
authors.forename: Kadeshia
authors.initials: K
authors.lastname: Dunn
authors.affiliation: Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelly
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.
authors.forename: Gamze
authors.initials: G
authors.lastname: Karaca
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Szak
authors.affiliation: Medway School of Pharmacy, University of Kent, Chatham, Kent, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Peppiatt-Wildman
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts; jeremy.duffield@biogen.com linda.burkly@biogen.com.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Research & Development, Biogen, Cambridge, Massachusetts; jeremy.duffield@biogen.com linda.burkly@biogen.com.|Division of Nephrology, Departments of Medicine & Pathology, and Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D000074049:Cytokine TWEAK; D018450:Disease Progression; D005355:Fibrosis / Q000209:etiology; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology*; D051379:Mice; D058628:Myofibroblasts / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000502:physiology*
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C000613300:Tnfrsf12a protein, rat; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors
keywords: Alport nephropathy; chronic; kidney disease; myofibroblast; pericyte; vascular biology