Serafini et al. showed that both TWEAK and Fn14 were upregulated in postmortem MS brain sections (29). Furthermore, this increase was related to the degree of inflammation and demyelination. Perivascular and intrameningeal macrophages, microglia, and astrocytes were the main sources of TWEAK, with a different contribution according to lesion location and degree of inflammation. Fn14 was expressed by neurons and astrocytes in the cortex of highly infiltrated MS brains (29). The absence of TWEAK/Fn14 expression in healthy brain reinforces the idea that TWEAK/Fn 14 pathway could play a role in MS pathogeny. In blood, Desplat-Jégo et al. demonstrated that mTWEAK was expressed at the cell surface of monocytes derived from MS patients but not from non-MS patients (18). In MS, such mTWEAK-expressing monocytes could represent immune cells that infiltrate CNS by interacting with Fn14 molecules at the membrane of BBB endothelial cells. In the same study, sTWEAK serum and cerebrospinal fluid levels were similar in MS and non-MS patients (18), suggesting that sTWEAK is not a reliable diagnosis MS biomarker.

Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is the best-characterized animal model of MS. In chronic EAE induced in C57Bl/6 mice, TWEAK transcript levels increased in the spinal cord (24). Moreover, transgenic mice overexpressing sTWEAK developed a more severe EAE than wild-type mice (24). Besides, in cuprizone-treated mice, a model of demyelination/remyelination, TWEAK and Fn14 transcription were upregulated during both demyelination and remyelination phases (30).

Treated with cuprizone TWEAK-knock-out mice displayed a significant delay in microglia accumulation and in demyelination phases (30). Reinforcing the role of TWEAK/Fn14 in MS, our team showed that EAE severity and CNS leukocyte infiltration were reduced in mice treated with blocking monoclonal anti-TWEAK antibody after the priming phase (31). Moreover, an Fn14-TNF-related apoptosis-inducing ligand (TRAIL) fusion protein was designed to simultaneously block endogenous TWEAK and mediate TRAIL inhibitory signals on activated T cells (32). Injected in EAE-mice, this protein reduced EAE severity (32, 33). Additionally, vaccinating mice or rats with TWEAK extracellular domain or with Fn14 induced the production of specific inhibitory antibodies. Such treatment was associated with reduced inflammatory spinal cord infiltration and with clinical amelioration during EAE (34). However, in humans, a raising question is the relevance of targeting TWEAK in MS when anti-TNF-α has failed to improve disease status (35). One could argue that the TWEAK/Fn14 pathway could also play a role in neuroprotection. In this way, Iocca et al. observed a modest but significant delay in remyelination of TWEAK-knock-out mice treated with cuprizone. However, this marginal delay did not result in prolonged defect in remyelination (30). Later, Echeverry et al. described a TNF-α-dependent neuroprotective effect of TWEAK in another NI model (13), but data in MS are lacking. Further studies are then needed to definitively establish that TWEAK is a relevant therapeutic target in MS.

Putterman et al. observed an increased expression of TWEAK and Fn14 in the cerebral cortex of the MRL/lpr mouse strain with NPSLE (37, 38). Furthermore, knocking out Fn14 in this strain (i) significantly improved cognitive function and (ii) decreased depression and anhedonia in comparison with MRL/lpr wild-type mice. These clinical parameters were associated with decreased levels of proinflammatory cytokines and preserved BBB integrity (37). Further, CNS anatomopathological studies in these mice showed (i) a reduction of fibronectin deposition and inducible form of nitric-oxyde synthase (iNOS) production, (ii) a diminution of immune infiltrates, and (iii) a decrease of IgG deposition and complement activation (39). Finally, reduced cortex neuronal degeneration, apoptosis, and gliosis were associated with improved cognitive functions in such mice (40).

These results were consolidated by intracerebroventricular injection of Fc-TWEAK in non-autoimmune mice. Just like MRL/lpr strain, these mice developed NPSLE symptoms, associated with high levels of TWEAK pathway downstream components, complement and iNOS activation, IgG brain deposition, neurodegeneration, and apoptosis (39). Trysberg et al. suggested that NPSLE could be associated with high levels of MMP-9 and sTWEAK in cerebrospinal fluid (41, 42). They also found a significant correlation between intrathecal MMP-9 and levels of tau (a neuronal degeneration marker) and glial fibrillary acidic protein (an astrocytic degeneration marker) (41). These results suggest that TWEAK/Fn14 interaction might be involved in brain damages during NPSLE since it promotes synthesis and activation of MMP-9 in CNS (27). Nevertheless, a recent study concluded that TWEAK levels in serum and cerebro-spinal fluid did not seem relevant biomarkers for NPSLE (43).

Finally, these findings highly support the involvement of TWEAK/Fn14 interaction in NPSLE pathogenesis and symptom occurrence.

Experimental focal cerebral ischemia was associated with an increase in TWEAK and Fn14 mRNA levels (44) and with BBB disruption (45, 46). In this context, TWEAK-induced NF-κB activation resulted in both astrocytic chemokine (C-C motif) ligand-2 (CCL-2) expression, leading to polynuclear neutrophil recruitment into the damaged zone, and in upregulation of MMP-9 activity (45–47). The effective inhibition of this neuroinflammatory process by Fn14-Fc decoy injections (46, 48) was associated with a reduced ischemic zone and hastened motor function recovery (46). Stroke patients displayed significantly elevated TWEAK serum levels and, in postmortem stroke human brains, elevated Fn14 mRNA levels were associated with upregulated Fn14 immunostaining in the ischemic zone (49).

Hypoxic-preconditioning of mice or cultured neurons promotes neuron survival and reduces ischemic lesion volume. In this context, TWEAK and Fn14 levels increase. Moreover, the protective effect of hypoxic preconditioning was abrogated in TWEAK or Fn14 KO mice and restored in cultured neurons after addition of TWEAK (13). This suggests that the TWEAK/Fn14 pathway contributes to the protective effect of hypoxic preconditioning. This is likely mediated by neuronal TNF-α and the activation of the MAPK pathway, resulting in the inactivation of the Bcl-2-associated death promoter protein (13).

These results suggest that a relevant therapeutic strategy would be administration of TWEAK in order to protect the brain in patients at high risk of stroke.

Tumor necrosis factor-like weak inducer of apoptosis upregulates Fn14 in migrating glioblastoma cells. This overexpression correlates with tumor aggressiveness and poor outcome (50, 51). In this way, Fn14 expression may help classifying glioma histological subtype (52). Moreover, canonical NF-κB pathway, stimulated by TWEAK, promotes Rac1 and Cdc42 expression, key mediators in the regulation of glioblastoma cell migration and invasion (51, 53, 54). Interestingly, Cherry et al. showed that MMP-9 inhibition abolished TWEAK-induced glioma invasion (55).

Therapeutic strategies targeting Fn14 in malignant cells have been evaluated. In these preclinical studies, manipulating Fn14 expression levels or suppressing TWEAK-Fn14-NFκB-dependent signaling decreased glioblastoma cell invasion capacity (56, 57). However, further experiments are needed to evaluate whether these strategies can significantly impact patients’ survival.

Bowerman et al. used a model of transgenic mice overexpressing human mutant SOD1 and recapitulating the main traits of ALS to study TWEAK/Fn14 involvement in ALS (15). In this model, mTWEAK was upregulated in the spinal cord and it induced astrocyte proliferation and IL-6 release. TWEAK and Fn14 were also found in skeletal muscle with different patterns of expression linked to disease development. In this study, the authors demonstrated a TWEAK induced-motor neuron death (15). Surprisingly, it was mediated by TWEAK interaction with CD163, a putative alternative TWEAK receptor. This neuronal death involved caspase-3 activation and was totally independent of Fn14. This work is the first implicating CD163 in mediating TWEAK effects in an inflammatory neurological disease. CD163 is a member of the scavenger receptors and is exclusively expressed by monocytes and macrophages. Increasing in vivo and in vitro evidences suggest that the interaction between TWEAK and CD163 may affect the development of atherosclerosis and related diseases (59).

Tumor necrosis factor-like weak inducer of apoptosis deletion reduced astrogliosis and microgliosis in the spinal cord, which substantiated the implication of the TWEAK pathway in ALS. However, muscle pathology was only partially reduced and TWEAK deletion did not prevent motor deterioration nor increase life span. In the same way, anti-TWEAK antibodies injected in ALS mice decreased microgliosis without improving motor functions. Bowerman et al. thus proposed a model combining the action of peripheral and central TWEAK, which could both contribute to the sustained activation of microglia in ALS (15).

This work suggests that blocking TWEAK in ALS is interesting but not sufficient and requires being included in a combinatory therapeutic approach.

Parkinson’s disease is a neurodegenerative pathology characterized by movement impairment due to dopaminergic loss in the nigrostriatal pathway. It may also have a neuroinflammatory component, where NF-κB may play a dual role, both promoting and protecting against neurodegeneration (60). The role of TWEAK itself has been studied in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model and in Parkinson’s disease human brain samples (61). There was no difference in substantia nigra TWEAK concentration between MPTP mice, Parkinson’s disease patients, and controls. While TWEAK or Fn14-KO failed to prevent MPTP toxicity, anti-TWEAK antibodies treatment attenuated the MPTP-induced death of dopaminergic neurons (61). These apparently conflicting results could be explained in part by existing compensatory systems, including the TNF-α pathway, since TNF is expressed in microglia of Parkinson’s disease patients.

Neuroinflammation is highly suspected to be involved in psychiatric pathologies like schizophrenia or bipolar disorder. Recently, TWEAK plasma levels of patients suffering from schizophrenia were compared with controls. Although no difference was shown globally, TWEAK levels in male patients were significantly lower than in male controls, suggesting TWEAK involvement in subgroups of schizophrenia patients (62). In bipolar disorder, conflicting results were observed, perhaps due to the heterogeneity in patients’ groups: Cingi et al. measured lower TWEAK plasma levels compared to healthy controls (63), while Barbosa et al. described increased concentrations, regardless of the mood (64). Nevertheless, as the interest for studying TWEAK/Fn14 pathway in psychiatric diseases is very recent, further studies will certainly be available soon.

This mini-review reveals that the TWEAK/Fn14 pathway modulates NI in neurodegenerative, immune, ischemic, and malignant CNS inflammatory diseases. In fact, as supported by both animal and human in vitro and in vivo studies, TWEAK/Fn14 can modulate NI by activating canonical and non-canonical NF-κB pathways but also MAPK signaling. Then, expression or release of inflammatory cytokines, chemokines, and adhesion molecules are upregulated and astrogliosis and microgliosis occur. Additionally, MMP-9 secretion is stimulated and reinforces BBB disruption and tissue remodeling. Note that monoclonal anti-TWEAK antibodies have been injected in patients in phase I clinical studies. In healthy volunteers or patients with solid tumors or rheumatoid arthritis, they (i) displayed a classical therapeutic antibody pharmacokinetic pattern, (ii) were associated with a favorable safety profile, and (iii) induced a decrease in circulating TWEAK serum level (65–68). Additionally, in these studies, TWEAK/Fn14 pathway inhibition yielded encouraging results, such as reduced clinical and biological inflammatory markers, including sTWEAK. All these data support the concept that the TWEAK/Fn14 axis represents a promising therapeutic target for modulating inflammation, including NI.