TWEAK/Fn14 Signaling in Inflammation and Tissue Remodeling

TWEAK (tumour necrosis factor-like weak inducer of apoptosis) and its sole receptor Fn14 (fibroblast growth factor-inducible 14) form a pivotal cytokine–receptor pair that regulates a spectrum of cellular responses in health and disease. Upon binding of soluble or membrane-bound TWEAK, Fn14 recruits TNF receptor-associated factors and activates both canonical and non-canonical NF-κB pathways, as well as MAPK and PI3K cascades. Transient TWEAK/Fn14 activation promotes wound repair, angiogenesis and extracellular matrix turnover, whereas sustained or excessive signalling drives chronic inflammation, fibrosis and aberrant tissue remodelling. This dualistic nature underlies its involvement in diverse pathologies including autoimmune disorders, cardiovascular remodelling, metabolic disease and tissue injury after ischaemia. Membrane dynamics and ligand form (soluble versus membrane-bound) further refine downstream outcomes, influencing cell fate decisions such as proliferation, differentiation and apoptosis. Emerging evidence also implicates cross-talk with antioxidant defences and immune-regulatory T cell subsets, highlighting the system’s complexity. The widespread expression of Fn14 in injured or inflamed tissues, together with the availability of soluble decoy receptors and blocking antibodies, renders the TWEAK/Fn14 axis an attractive target for therapeutic intervention and biomarker development.

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TWEAK/Fn14 Signaling in Inflammation and Tissue Remodeling publication trend

The graph below shows the total number of articles in tweak/fn14 signaling in inflammation and tissue remodeling across all publications each year (not limited to Nature Index journals).

Technical terms

TWEAK: A cytokine in the TNF superfamily that binds Fn14 to regulate cell survival, proliferation and inflammation.

Fn14: The small type I transmembrane receptor for TWEAK, upregulated in injured or inflamed tissues.

Canonical NF-κB pathway: A signalling cascade activated by TWEAK/Fn14 leading to rapid IκB degradation and RelA/p50 nuclear translocation.

Non-canonical NF-κB pathway: A slower route involving NIK-dependent processing of p100 to p52 and RelB/p52 activation.

Nrf2/HO-1 pathway: An antioxidant response controlled by Nrf2 that induces heme oxygenase-1 to counteract oxidative stress.

Th17/Treg balance: The equilibrium between pro-inflammatory T helper 17 cells and anti-inflammatory regulatory T cells critical for immune homeostasis.

CD163: A macrophage-expressed scavenger receptor that binds soluble TWEAK, modulating tissue regeneration and inflammatory signalling.

References

1. TWEAK/Fn14 disrupts Th17/Treg balance and aggravates conjunctivitis by inhibiting the Nrf2/HO-1 pathway in allergic conjunctivitis mice. Molecular Medicine (2024).
2. Antibody-based soluble and membrane-bound TWEAK mimicking agonists with FcγR-independent activity. Frontiers in Immunology (2023).
3. The TWEAK/Fn14/CD163 axis—implications for metabolic disease. Reviews in Endocrine and Metabolic Disorders (2021).
4. TWEAK, a New Secreted Ligand in the Tumor Necrosis Factor Family That Weakly Induces Apoptosis*. Journal of Biological Chemistry (1997).
5. CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury. Nature Communications (2015).
6. TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFκB. Cell Death & Disease (2016).
7. TWEAK Induces Angiogenesis and Proliferation of Endothelial Cells*. Journal of Biological Chemistry (1999).