Out of the TWEAKlight: Elucidating the Role of Fn14 and TWEAK in Acute Kidney Injury☆☆,
Section snippets
Tweak, Fn14, And CD163
TWEAK activates the Fn14 receptor and is scavenged by macrophage-derived CD163 (Fig. 1). Described in 1997 as a weak inducer of cell death, TWEAK is the sole cytokine signaling through Fn14.12, 13 Type II transmembrane protein TWEAK is cleaved to generate a soluble cytokine. Both soluble and membrane TWEAK activate Fn14.12, 14, 15 The Fn14 intracellular domain is the shortest of the TNFR superfamily and lacks the characteristic death domain, but it contains TNFR-associated factor–binding
Tweak Actions On Renal Tubular Cells
TWEAK has actions on intrinsic kidney cells of potential pathophysiological relevance through Fn14-receptor signaling (Figure 2, Figure 3), including in podocytes and kidney fibroblasts.6, 39 However, the effects of TWEAK in tubular cells have been explored in the most detail and are discussed here in the context of AKI.
In cultured murine tubular cells, TWEAK activates MAPK such as extracellular signal-regulated kinase1/2 (ERK1/2) and p38 MAPK, phosphoinositide 3-kinase/Akt, JAK2 kinase, and
Tweak Interaction With Other Cytokine Systems And Toxins
Cell responses to TWEAK may be modified by the simultaneous presence in the cellular milieu of additional factors, cytokines, and toxins, and TWEAK may modulate other cytokine systems.
The proinflammatory effect of TWEAK on cultured tubular cells is enhanced by the simultaneous presence in the cell environment of additional inflammatory mediators, such as CXCL16, TNFα, and interferon-γ.40, 43 TWEAK alone does not promote renal tubular cell apoptosis.30, 45 However, an inflammatory milieu
Profibrotic Actions Of Tweak In Kidney Cells
The AKI-to-CKD transition is characterized by the development of kidney fibrosis and TWEAK may have a specific role at several steps of the process, beyond any indirect action resulting from inflammation and cell death (Fig. 3). Kidney fibrosis involves myofibroblast proliferation, increased extracellular matrix (ECM) synthesis and deposition, and transdifferentiation of tubular epithelial cells by epithelial to mesenchymal transition (EMT). Although the contribution of EMT to fibroblast
Systemic Tweak Effects On Healthy Kidneys
Systemic events leading to increased circulating TWEAK levels, as observed in sepsis,26 may impact normal kidneys. In general, actions of systemic TWEAK administration to experimental animals mirror results obtained in cultured renal cells. A single parenteral TWEAK injection in mice31, 41, 42, 45, 60, 61 induced tubulointerstitial inflammation, decreased kidney klotho and PGC-1α expression, and promoted tubular cell proliferation within 4 to 24 hours.31, 44 TWEAK activated canonical (RelA) and
Tweak As A Promoter Of Aki And Of The Aki-To-Ckd Transition
The potential role of TWEAK and Fn14 in kidney injury has been explored in experimental AKI using genetic approaches or antibodies to target TWEAK or Fn14 (Table 2). This has uncovered functional in vivo evidence for the role of TWEAK/Fn14 in AKI and in the AKI-to-CKD transition.7, 39, 41, 42, 43, 44, 45
Tubular cell Fn14 is up-regulated within 24 hours in experimental AKI induced by a folic acid overdose or by renal ischemia-reperfusion, and at 3 days after ureteral obstruction as well as in
Tweak/Fn14 Targeting In The Clinic
Phase 1 and phase 2 clinical trials exploring TWEAK/Fn14 targeting have been completed or terminated in autoimmune inflammation, cancer, and muscle atrophy (Table 1). A phase I dose-ranging clinical trial in rheumatoid arthritis showed that a single intravenous of the neutralizing anti-TWEAK antibody BIIB023 decreased serum TWEAK to undetectable levels for up to a month, and tended to decrease circulating inflammation mediators.62 However, a phase 2 randomized placebo-controlled clinical trial
Aki As A Therapeutic Target For Clinical Trials
An increasing body of evidence suggests that TWEAK has a deleterious role in sterile inflammation–associated kidney injury through actions on intrinsic renal cells that include further promotion of inflammation and cell death. The recent (October 2015) termination of a phase 2 anti-TWEAK antibody trial, which targeted autoimmune kidney disease, is bad news. However, the pathogenesis of AKI is different from lupus nephritis, and TWEAK/Fn14 targeting in oncology and other fields may provide
References (73)
- et al.
TWEAK, a multifunctional cytokine in kidney injury
Kidney Int
(2011) - et al.
Fn14 in podocytes and proteinuric kidney disease
Biochim Biophys Acta
(2013) - et al.
Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis
Clin Immunol
(2012) - et al.
TWEAK stimulation of kidney resident cells in the pathogenesis of graft versus host induced lupus nephritis
Immunol Lett
(2009) - et al.
TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis
J Biol Chem
(1997) - et al.
Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human
J Biol Chem
(2006) - et al.
Full-length, membrane-anchored TWEAK can function as a juxtacrine signaling molecule and activate the NF-kappaB pathway
J Biol Chem
(2010) TWEAK/Fn14 axis: the current paradigm of tissue injury-inducible function in the midst of complexities
Semin Immunol
(2014)- et al.
TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease
Cytokine
(2007) - et al.
Changes in fat mass correlate with changes in soluble sCD163, a marker of mature macrophages, in patients with CKD
Am J Kidney Dis
(2006)
The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration
J Biol Chem
Cytokine cooperation in renal tubular cell injury: the role of TWEAK
Kidney Int
Direct targeting of fibroblast growth factor-inducible 14 protein protects against renal ischemia reperfusion injury
Kidney Int
TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras-dependent proliferation of cultured renal fibroblast
Biochim Biophys Acta
TWEAK (tumor necrosis factor-like weak inducer of apoptosis) activates CXCL16 expression during renal tubulointerstitial inflammation
Kidney Int
Klotho modulates the stress response in human senescent endothelial cells
Mech Ageing Dev
Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure
Kidney Int
Role of epidermal growth factor receptor in acute and chronic kidney injury
Kidney Int
Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury
Am J Pathol
TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells
Cytokine
Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis
Clin Ther
Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th Acute Dialysis Quality Initiative consensus conference
Kidney Int
International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology
Lancet
Acute kidney injury: an increasing global concern
Lancet
Acute kidney injury
Lancet
The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting
Nat Rev Drug Discov
The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases: focus on inflammatory bowel diseases
J Leukoc Biol
TWEAK/Fn14 pathway: an immunological switch for shaping tissue responses
Immunol Rev
TWEAK and the progression of renal disease: clinical translation
Nephrol Dial Transplant
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice
Arterioscler Thromb Vasc Biol
Deficiency of fibroblast growth factor-inducible 14 (Fn14) preserves the filtration barrier and ameliorates lupus nephritis
J Am Soc Nephrol
TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the chronic graft-versus-host model of systemic lupus erythematosus
J Immunol
Soluble and transmembrane TNF-like weak inducer of apoptosis differentially activate the classical and noncanonical NF-kappa B pathway
J Immunol
A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications
J Immunol
CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury
Nat Commun
Additive effects of soluble TWEAK and inflammation on mortality in hemodialysis patients
Clin J Am Soc Nephrol
Cited by (0)
- ☆☆
Financial support: Supported by FIS PI13/00047, PI14/0041, PI15/01460, CP14/00133, CP12/03262, PI15/00298, Instituto de Salud Carlos III-Redes Tematicas de Investigacion Cooperativa en Salud (ISCII-RETIC), REDinREN, Fondo Europeo de Desarrollo Regional (FEDER) funds, RD12/0021, Sociedad Española de Nefrologia, Fundacion Renal Iñigo Alvarez de Toledo (FRIAT), and Comunidad de Madrid/Consorcio de Investigacio de Fracaso Renal Agudo (CIFRA) S2010/BMD-2378. Salary support was provided by Fondo de Investigacion Sanitaria (FIS) (M.D.S.-N.) (Miguel Servet), Ana Belén Sanz (ABS) (Miguel Servet), Adrian Mario Ramos (AMR) (Miguel Servet-II), and Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/Comunidad de Madrid (CM)) (A.O.).
Conflicts of interest statement: none.