Regulation of Neuroinflammation: What Role for the Tumor Necrosis Factor-Like Weak Inducer of Apoptosis/Fn14 Pathway?

Abstract

Observed in many central nervous system diseases, neuroinflammation (NI) proceeds from peripheral immune cell infiltration into the parenchyma, from cytokine secretion and from oxidative stress. Astrocytes and microglia also get activated and proliferate. NI manifestations and consequences depend on its context and on the acute or chronic aspect of the disease. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 pathway has been involved in chronic human inflammatory pathologies such as neurodegenerative, autoimmune, or malignant diseases. New data now describe its regulatory effects in tissues or fluids from patients with neurological diseases. In this mini-review, we aim to highlight the role of TWEAK/Fn14 in modulating NI in multiple sclerosis, neuropsychiatric systemic lupus erythematosus, stroke, or glioma. TWEAK/Fn14 can modulate NI by activating canonical and non-canonical nuclear factor-κB pathways but also by stimulating mitogen-activated protein kinase signaling. These downstream activations are associated with (i) inflammatory cytokine, chemokine and adhesion molecule expression or release, involved in NI propagation, (ii) matrix-metalloproteinase 9 secretion, implicated in blood–brain barrier disruption and tissue remodeling, (iii) astrogliosis and microgliosis, and (iv) migration of tumor cells in glioma. In addition, we report several animal and human studies pointing to TWEAK as an attractive therapeutic target.

Cyclic Peptides in Neurological Disorders: The Case of Cyclo(His-Pro)

“…Usually triggered by peripheral inflammation, the term describes a wide range of immune responses by the central nervous system cells, such as microglia, astrocytes, and blood brain barrier, each linked by a dynamic crosstalk. In the presence of prolonged and sustained inflammation, the neuroinflammatory response results in synaptic impairment, neuronal death, and eventually neurodegeneration (Boulamery and Desplat-J ego, 2017;Lyman et al, 2014;Rustenhoven et al, 2017). As described previously, the effects of CHP could counteract this pathogenic state in two ways: by activating Nrf2 and inducing HO-1 activity, the compound might simultaneously drive a protective antioxidant response, mitigating oxidative stress damage, while inhibiting NF-κB signaling, reducing damage associated with inflammation (Minelli et al, 2012).…”

TRAIL, OPG, and TWEAK in kidney disease: biomarkers or therapeutic targets?

“…Generally, the activation of the TWEAK/Fn14 pathway is strictly dependent on Fn14 up-regulation. In normal (healthy) conditions, both TWEAK and Fn14 appear to be expressed at low levels; by contrast, in various disease conditions, including autoimmune and inflammatory/neuro-inflammatory diseases [82][83][84][85][86][87] as well as several types of cancer [88][89][90][91][92][93], both Fn14 and TWEAK expressions are up-regulated.…”

A novel Tweak/ Stat1/ Snhg3 positive feedback circuit contributes to the glial cell activation in temporal lobe epilepsy mice

“…The TWEAK/Fn14 pathway has been shown to be involved in chronic human inflammatory pathologies such as neurodegeneration, autoimmunity or malignant diseases [10]. TWEAK/Fn14 can modulate neuroinflammation by activating the canonical and non-normative NF-κB pathways, as well as by stimulating mitogen-activated protein kinase signaling [10]. TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway [36].…”

“…Soluble TWEAK can modulate the expression of proteins that are involved in inflammation and opening of the blood brain barrier [9]. In murine and human astrocytes, the TWEAK/Fn14 pathway stimulates reactivity when cell proliferation is activated and inflammatory factors are produced [10]. TWEAK/Fn14 pathway is involved in human neurodegenerative disease.…”