Fibroblast growth factor–inducible-14 (Fn14) was described in fibroblasts as an immediate-early response gene to growth factors. Fn14 is a member of the TNF receptor superfamily (TNFRSF), also termed TNFRSF12A. The only ligand for Fn14 is the cytokine TWEAK (Wiley and Winkles 2003), and Fn14 is the only signaling receptor for TWEAK. Both have been targeted therapeutically in humans.
Alternative splicing generates a smaller isoform of Fn14 which lacks the extracellular, TWEAK-binding domain (Brown et al. 2013).
Fn14 is expressed at low level in numerous cell types and tissues, including diverse epithelial cells, endothelial cells, vascular cells, and fibroblasts (Burkly et al. 2007). However, Fn14 is strongly upregulated in response to stress or injury triggered by factors such as cytokines, growth factors, and toxins (Sanz et al. 2016). Moreover, Fn14 is upregulated during tissue regeneration in liver, kidney, pancreas, and skeletal muscle (Karaca et al. 2014; Sanz et al. 2009; Enwere et al. 2014; Wu et al. 2013).
In silico, the Fn14 promoter contains consensus sequences for various transcription factors, but only SP1 and AP1 showed DNA-binding activity and were involved in Fn14 upregulation in denervated skeletal muscle (Tajrishi et al. 2014b). The Fn14 promoter also contains a functional retinoic acid receptor (RAR) site, and RAR signaling mediates Fn14 expression in hepatocellular carcinoma (Wang et al. 2012). The Fn14 promoter also contains a CpG island close to the transcription start site, and expression is also regulated by DNA methylation. Methylation of CpG islands by DNA methyltransferases (Dnmts) leads to gene silencing. Dnmt3 downregulation in denervated muscle leads to Fn14 promoter hypomethylation and Fn14 overexpression (Tajrishi et al. 2014b).
Fn14 is also regulated at the posttranslational level. Similar to other members of the TNFRSF, Fn14 interaction with TWEAK leads to receptor internalization and degradation. However, Fn14 also undergoes rapid and constitutive turnover independent of TWEAK (Gurunathan et al. 2014). This data has physiological relevance since changes in Fn14 trafficking could lead to Fn14 stabilization and increase TWEAK-Fn14 binding and signaling. Soluble Fn14 (sFn14) is increased in plasma and urine of mouse models of kidney diseases and in patients with diabetic nephropathy. However, the mechanism that generates sFn14 is unknown. It may depend on receptor shedding since this is common in the TNFR family. The role of sFn14 is also unidentified; there are two hypotheses: it may inhibit TWEAK actions as a decoy receptor or preserve circulating TWEAK, thus increasing TWEAK activity. Further studies are necessary to understand the generation and the role of sFn14 (Sharif et al. 2016).
Upon TWEAK binding, the Fn14 TRAF-binding domain associates with TRAFs 1, 2, 3, and 5, activating various MAPKs, including MAP3K14, as well as Ras, PI3K/Akt, JAK2-STAT, and the canonical and noncanonical pathways for NFκB activation (Brown et al. 2003; Ortiz et al. 2017; Ucero et al. 2013a, b). TWEAK independent-Fn14 signaling might occur when Fn14 levels are very high, although this has not been tested directly (Winkles 2008). In this regard, overexpression of the alternative spliced Fn14 isoform lacking the extracellular domain resulted in NFκB activation, indicating that TWEAK-independent Fn14 signaling does occur (Brown et al. 2013). This information may help design better therapeutic approaches against the TWEAK/Fn14 axis.
TWEAK/Fn14 signaling may also recruit EGFR and FGFR-1 signaling pathways.
In tubular epithelial cells, the TWEAK/Fn14 interaction induces EGFR transactivation by activating the ADAM17 sheddase and thus promoting the release of membrane-bound EGFR ligands. TWEAK/Fn14-induced EGFR transactivation mediates inflammatory responses to TWEAK dependent of MAPKs, whereas it did not affect TWEAK-induced NFκB activation (Rayego-Mateos et al. 2013). Moreover, a positive correlation between Fn14 expression and EGFR activation was observed in lung cancer (Whitsett et al. 2012).
There is a physical interaction between Fn14 and FGFR-1 that is increased by their respective ligands TWEAK and FGF-1 (Novoyatleva et al. 2014). Thus, in cardiomyocytes Fn14 and FGFR-1 act synergistically to promote cell cycle reentry.
Proliferation: Regeneration and Fibrosis
Fn14-mediated proliferation may be beneficial and contribute to liver, pancreas, and kidney regeneration following surgical mass reduction (Karaca et al. 2014; Sanz et al. 2009; Wu et al. 2013). After partial hepatectomy, Fn14 expression is increased, and TWEAK/Fn14 signaling promotes hepatocyte and hepatic progenitor cells proliferation (Karaca et al. 2014). A similar result were observed after partial pancreatectomy, since Fn14 deficiency delays pancreatic regeneration and impairs β-cell neogenesis from ductal epithelium (Wu et al. 2013), and in the remnant kidney following unilateral nephrectomy, where TWEAK deficiency impaired and exogenous TWEAK promoted tubular cell proliferation (Sanz et al. 2009). Thus, Fn14 activation could have beneficial effects after noninflammatory loss of liver, kidney, or pancreatic mass.
However, sustained activation of Fn14 may induce fibroblast proliferation and promotes fibrosis, as is observed in kidneys, liver, heart, and muscle. In kidneys, Fn14 activation induces fibroblast proliferation, leading to more severe experimental renal fibrosis in a model of sustained renal injury (Ucero et al. 2013a). Fn14 is also upregulated in liver myofibroblats from patients with fatty liver disease (Wilhelm et al. 2016). Moreover, in the heart, Fn14 activation induces cardiac fibroblast proliferation and myofibroblast differentiation, while Fn14 deletion reduces myocardial fibrosis in experimental heart failure (Ucero et al. 2013a). The molecular pathways involved in Fn14-induced fibrosis include NFκB, RhoA, TGF-β, and Ras/ERK pathway (Chen et al. 2012, 2015; Novoyatleva et al. 2013; Ucero et al. 2013a).
Fn14 activation can also promote cell death. Indeed, TWEAK was named for its capacity to induce apoptosis in interferon γ-treated HT29 adenocarcinoma cells (Chicheportiche et al. 1997). TWEAK also promotes death in neurons, monocytes, tumor cell lines, resident renal cells, and others, but this usually requires Fn14 upregulation driven by proinflammatory stimuli (Michaelson and Burkly 2009; Ortiz et al. 2009). Usually, Fn14 has been related with apoptosis, but in recent years it was also shown to promote necroptosis (Linkermann et al. 2013).
As an example, in an inflammatory medium, Fn14 promotes apoptosis in renal tubular cells. In this context, caspase inhibition prevents features of apoptosis but does not prevent overall cell death (Justo et al. 2006). Indeed, caspase inhibition increases oxidative stress-dependent cell death. However, necrostatin-1, a small molecule inhibitor of necroptosis, prevents this form of cell death suggesting that Fn14 may under certain conditions promote necroptosis (Linkermann et al. 2013). In this regard, TWEAK/Fn14 blockade prevented cell death in different models of tissue injury, such as experimental acute kidney injury or cerebral ischemia (Sanz et al. 2016). The capacity of Fn14 to induce cell death in tumor cells has become a strategy for cancer treatment.
Fn14 has proinflammatory actions in numerous cell types and tissues and this is mediated mainly by the canonical NFκB pathway. However, MAPKs including MAP3K14, the noncanonical NFκB pathway, JAK2/STAT and EGFR transactivation may mediate TWEAK/Fn14 inflammatory response (Ortiz et al. 2017; Rayego-Mateos et al. 2013; Ucero et al. 2013b; Valiño-Rivas et al. 2016). Fn14 activation can also induce the expression of molecules that amplify the inflammatory response, such as CXCL16 and HMGB1. Thus, in renal tubular cells CXCL16 increased inflammatory response of TWEAK (Izquierdo et al. 2012). In macrophages, Fn14 may promote M1 macrophages differentiation throughout HMGB1 release (Moreno et al. 2013).
Independently of the intracellular pathways involved, Fn14-induced inflammation has a pathophysiological relevance, since targeting TWEAK/Fn14 reduces inflammatory responses in experimental models including systemic lupus erythematosus (SLE) and lupus nephritis, acute colitis, acute kidney injury, and proteinuric kidney disease (Doerner et al. 2016; Dohi et al. 2014; Sanchez-Niño et al. 2013; Xia et al. 2014).
Reduction of Tissue and Cell Protective Factors
In addition to promoting an NFκB-mediated proinflammatory response, TWEAK/Fn14 also recruit the canonical NFκB pathway and epigenetic mechanisms such as histone deacetylases (HDAC) to repress the expression of genes with protective functions, such as Klotho, an antiaging hormone, and PGC-1α, a key mitochondrial biogenesis regulator (Moreno et al. 2011), (Ruiz-Andres et al. 2016). Both genes, Klotho and PGC-1α, have nephroprotective properties and Fn14 represses their expression in vivo during inflammatory renal diseases.
Studies in Experimental Models and Human Diseases
The biological processes mediated by TWEAK/Fn14 described above suggest that this system may have a pathophysiological relevance in disease conditions in which these processes play a key role. In this regard, functional experimental studies and descriptive human approaches have characterized the role of TWEAK/Fn14 in disease.
Systemic Lupus Erythematosus (SLE)
SLE is a multisystem autoimmune disease featuring autoantibody production, with involvement of kidneys (lupus nephritis), skin inflammation, and neuropsychiatric disease, among others. Functional experimental in vivo studies suggest the involvement of Fn14 in these manifestations (Zhao 2007). Functional in vivo studies disclosed a role of Fn14 in nephritis in the chronic graft-vs-host model of SLE but this model may not reflect well the human disease. The role of Fn14 was confirmed in spontaneous murine lupus nephritis in MRL/lpr mice. In this model, Fn14 deficiency in renal cells preserved renal function and reduced proteinuria, inflammation, and glomerular deposition of IgG, but circulating autoantibodies were not reduced (Xia et al. 2014). Fn14-Fc treatment also reduced glomerulonephritis and renal tubular damage in SLE model using sanroque mice (Min et al. 2016). However, Fn14 targeting reduced circulating antibodies in sanroque mice, contrary to the observation in MRL/lpr Fn14-KO mice (Xia et al. 2014; Zhao et al. 2007; Min et al. 2016). Thus, the effect of TWEAK/Fn14 on the immune response is controversial in mice and merits detailed studies in humans.
MRL/lpr Fn14-KO mice have significantly attenuated skin disease and markedly fewer skin infiltrating macrophages and T cells, comparing with MRL/lpr-WT mice Doerner et al. 2015, 2016). Interestingly, ultraviolet-B irradiation, a trigger for lupus skim manifestations, increased Fn14 levels in vitro and in vivo, and TWEK/Fn14 induced an inflammatory response in keratinocytes (Doerner et al. 2015).
The TWEAK/Fn14 system could also play a role in neuropsychiatric disease associated to SLE. Depressive-like behavior is an early manifestation of SLE that improved in MRL/lpr Fn14-KO mice compared with WT mice. Moreover, Fn14 deficiency also improved cognition in MRL/lpr mice (Wen et al. 2013). In this regard, Fn14 deficiency decreased the expression of proinflammatory mediators and the antibodies deposition in brain and improved blood-brain barrier integrity (Wen et al. 2013, 2015).
Collectively, these data suggest that TWEAK/Fn14 plays an important role in the pathogenesis of lupus and could be a therapeutic target. However, a randomized clinical trial of neutralizing anti-TWEAK antibodies as add-on, nephroprotective therapy on top of immune suppressants for lupus nephropathy failed to meet its primary end-point (ClinicalTrials.gov, Identifier:NCT01499355).
Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation that leads to cartilage and bone destruction. Human joint cells, such as synoviocytes, chondrocytes, and osteoblasts, express Fn14 and release inflammatory mediators in response to TWEAK (Burkly et al. 2007). Moreover, Fn14 expression is increased in synovial tissue of human rheumatoid arthritis and Fn14 activation induces proliferation and inflammation in synovial cell isolated from these patients (Burkly et al. 2007; Kamijo et al. 2008; van Kuijk et al. 2010). A phase I clinical trial of neutralizing anti-TWEAK antibodies in rheumatoid arthritis disclosed downmodulation of circulating inflammatory biomarkers (Wisniacki et al. 2013) (ClinicalTrials.gov, Identifier:NCT00771329). However, resources were shifted to address the therapeutic potential of TWEAK targeting in lupus nephropathy and clinical development was halted.
Fn14 is highly expressed in several tumors, including colorectal cancer, pancreatic carcinoma, non–small cell lung cancer, and ovarian cancer (Culp et al. 2010; Dai et al. 2009; Whitsett et al. 2012). Fn14 activation may favor tumor growth by promoting angiogenesis, cell survival, migration, and proliferation in some tumor cells. However, Fn14 also induces cell death in various tumor cells; indeed, the lethal effect of Fn14 is higher in tumor cells than in normal cells. In this regard, strategies under study to target the TWEAK/Fn14 axis in cancer are aimed at promoting tumor cell death. A humanized agonistic anti-Fn14 antibody, BIIB036, mimics many of the activities of TWEAK. BIIB036 induced tumor cell death in vitro, tumor regression in multiple xenograft models and in patient-derived primary tumors grown in mice, and had antimetastatic activity (Michaelson et al. 2011, 2012). Moreover, BIIB036 enhanced the efficacy of a variety of standard chemotherapeutics without added toxicity in xenograft models (Michaelson et al. 2012). Another agonistic humanized anti-Fn14 antibody, PDL192, shares some properties with BIIB036, and is in phase I safety study in patients with solid tumors (ClinicalTrials.gov, Identifier: NCT00738764). The antitumor activity of both antibodies is mainly mediated by antibody-dependent cellular cytotoxicity (ADCC) and activation of NF-κB signaling (Culp et al. 2010; Purcell et al. 2014; Zhou et al. 2013a). Fn14-targeted immunotoxins and granzyme B-anti-Fn14 constructs also showed antitumor effect in different xenograft models of cancer (Zhou et al. 2013a, b, 2014).
By contrast, a humanized anti-TWEAK neutralizing antibody, RG7212, blocked TWEAK-induced signaling and cytokine production, induced apoptosis, and inhibited tumor growth without toxicity in mice (Yin et al. 2013). A phase I clinical trial in patients with advanced solid tumors expressing Fn14 demonstrated that RG7212 was well tolerated and depleted TWEAK. In one patient, the tumor regressed (ClinicalTrials.gov, Identifier: NCT01383733). However, high exposures to RG7212 and high-tumor Fn14 might be required for the antitumor effect of TWEAK targeting (Meulendijks et al. 2016). Thus, the efficacy of anti-TWEAK treatment depends, in part, on the Fn14 levels.
Fn14 may be also a prognostic marker for cancer. Fn14 expression is upregulated in several tumor types and in some cases correlates with tumor progression. In human prostate cancer, Fn14 expression is negative in normal prostate epithelium, mildly positive in high-grade prostatic intraepithelial neoplasia foci, and very positive in prostate adenocarcinoma and correlates with poor clinical outcome (Huang et al. 2011; Sanz et al. 2012). Moreover, higher Fn14 expression in gastric cancer was associated with shorter survival and higher levels of the antiapoptotic protein BclxL (Kwon et al. 2012). In addition, bioinformatics analysis of metastatic tissues disclosed that Fn14 predicted brain metastasis progression in breast cancer patients (Martínez-Aranda et al. 2015).
Skeletal muscle atrophy or wasting is a major human morbidity associated to aging, chronic diseases, and inactivity/disuse conditions (Tajrishi et al. 2014c). Skeletal muscle atrophy is the result of either enhanced protein degradation or reduced synthesis or both. The TWEAK/Fn14 system is a major regulator of skeletal muscle mass (Tajrishi et al. 2014c). Fn14 expression is low in healthy skeletal muscle but increases under catabolic condition such as denervation (Mittal et al. 2010; Tajrishi et al. 2014b) amplifying TWEAK-induced NFκB activation and the degradation of specific muscle proteins (Mittal et al. 2010). Changes in the mitochondrial content can also promote muscle wasting. In this sense, Fn14 repressed PGC-1α expression and reduced the mitochondrial content, while PGC-1α overexpression blocked TWEAK-induced atrophy and reduced Fn14 expression.
The Fn14/TWEAK system has also been implicated in muscle atrophy associated to aging, myotonic dystrophy type 1 (DM1), and cancer-induced cachexia. Fn14-KO mice showed less inflammation, increased level of specific muscle proteins, and reduced levels of ubiquitinated proteins in skeletal muscle during aging than WT mice (Tajrishi et al. 2014a). Fn14 expression is upregulated in muscle tissue from DM1 patients and Fn14-KO mice showed better preserved skeletal muscle in experimental DM1 (Yadava et al. 2015). Cachexia is a metabolic disorder that includes progressive muscle wasting and is frequent in terminal stages of chronic diseases as cancer. Fn14 antagonistic antibodies prevented tumor-associated cachexia (Johnston et al. 2015).
Collectively, this data indicate that targeting the Fn14/TWEAK axis could be beneficial in muscle atrophy. Indeed, phase I clinical trials are studying BIIB023 neutralizing anti-TWEAK antibodies in patients with muscle atrophy and healthy male volunteers (Sanz et al. 2016) (ClinicalTrials.gov, Identifier:NCT01943513).
Vascular and Non-immune Renal Diseases
Accumulating evidences support a role for Fn14 in the pathogenesis of acute and chronic renal diseases since Fn14 on intrinsic renal cells, including podocytes, tubular cells, and renal fibroblasts, may facilitate inflammation, cell death, and fibrosis and decrease nephroprotective factors in culture and in vivo (Moreno et al. 2011; Ruiz-Andres et al. 2016; Sanz et al. 2014b, 2016). Targeting the TWEAK/Fn14 pathway protected from different forms of experimental acute kidney injury (Sanz et al. 2016) decreased glomerular inflammation in experimental nonimmune proteinuria (Sanchez-Niño et al. 2013; Valiño-Rivas et al. 2016) and decreased kidney fibrosis and inflammation in unilateral ureteral obstruction.
Chronic kidney disease progression may lead to end-stage kidney disease, requiring dialysis. Peritoneal dialysis uses the peritoneal membrane to clear waste products but peritonitis is a relatively common complication. In this regard, Fn14 expression was upregulated in peritoneal biopsies from peritoneal dialysis patients and correlated with mesothelial injury, fibrosis, and inflammation. Moreover, TWEAK administration induces peritoneal inflammation in mice (Sanz et al. 2014a).
Chronic kidney disease is associated with cardiovascular disease, particularly atherosclerosis and vascular calcification, which constitute the major causes of morbidity and mortality (Hénaut et al. 2016a). Fn14 can mediate renal and vascular injury associated to hyperlipidemia through proinflammatory cytokine production and macrophage recruitment (Muñoz-García et al. 2009). Furthermore, new mediators of Fn14-induced vascular damage have been described, such as Nox-2 and HMGB1 (Madrigal-Matute et al. 2015; Moreno et al. 2013). TWEAK activation of Fn14 promotes phosphate-induced human vascular smooth muscle cell calcification by favoring their osteogenic transition and increasing MMP9 activity through NFκB activation (Hénaut et al. 2016b). TWEAK/Fn14 also contributes to abdominal aortic aneurysms and Fn14-KO mice were protected from experimental aneurysms induced by elastase perfusion (Tarín et al. 2014).
Collectively, these data suggest that Fn14 could be a therapeutic target in both kidney and vascular disease.
Regardless the role of Fn14 in renal and vascular injury, Fn14 could be a potential biomarker of renal injury, as soluble sFn14 has been detected increased in urine and plasma of mice models of renal diseases and in patients where sFn14 levels correlates with disease severity (Sharif et al. 2016).
Fn14 is the only receptor for TWEAK, a cytokine of the TNF superfamily. Both are broadly expressed and may regulate cell proliferation, cell death, cell differentiation, and inflammation. The pathways activated by TWEAK/Fn14 signaling include alternative and classic NFκB, MAPKs, and PI3K/Akt pathway. Fn14 lacks the DD domain, characteristic of the TNFR superfamily, but signals through TRAF-binding domains. In vivo, Fn14 expression in healthy tissues is usually low but is significantly upregulated after injury. Functional studies targeting TWEAK and or Fn14 implicate the system in promoting acute and chronic tissue injury and in modulating cancer biology. Fn14 activation can also contribute to tissue repair and any therapeutic intervention should consider this possibility. Clinical targeting of TWEAK/Fn14 has proved safe in phase 1 and phase 2 studies. Development of the neutralizing anti-TWEAK antibody, BIIB023, for lupus nephritis is no longer pursued because of futility while PDL192 anti-Fn14 antibodies in subjects with advanced solid tumors (ClinicalTrials.gov, Identifier: NCT01499355, NCT00738764).
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