THE ROLE OF THE TWEAK/Fn14 AXIS IN THE TNF-α-INDUCED PATHOGENESIS OF RHEUMATOID ARTHRITIS

Farheen Sultan Shaikh

doi:10.7273/000006503

Rheumatoid arthritis (RA) pathogenesis involves dysregulated immune responses resulting in chronic synovial inflammation, eventually leading to joint destruction. Among the pivotal mediators of inflammation, tumor necrosis factor-alpha (TNF-α) is a master proinflammatory cytokine. Primarily secreted by activated immune cells like macrophages, TNF-α activates RA synovial fibroblasts (RASFs) to promote the secretion of chemokines and adhesion molecules, enhancing the recruitment of more inflammatory cells to the joints and contributing to the formation of destructive synovial pannus. TNF-α also stimulates the production of other cytokines like interleukin-1β (IL-1β) and interleukin-6 (IL-6), further amplifying the activation of RASFs through signal transduction. In clinical practice, TNF inhibitors (TNFi) have revolutionized the management of RA and other autoimmune conditions by effectively targeting TNF-α. However, despite the efficacy of these agents, a subset of patients exhibits primary or secondary resistance to TNF inhibition. This phenomenon of non-responsiveness to TNFi therapy highlights the need for a deeper understanding of the underlying mechanisms. The etiology of TNFi resistance in RA is multifactorial and involves various molecular, cellular, and immunological factors. Mechanisms implicated in non-responsiveness could be attributed to compensatory upregulation of alternative inflammatory pathways besides differential gene signature, receptor expression, and dysregulation of downstream signaling pathway. TWEAK (TNF-like weak inducer of apoptosis) is another cytokine from the TNF superfamily that interacts with its receptor fibroblast growth factor-inducible 14 (Fn14) to exacerbate inflammation in RA. In RA, unchecked TWEAK signaling, similar to TNF-α’s, causes increased phosphorylation of mitogen-activated protein kinases (MAPK), leading to the amplified transcription of the inflammatory genes. Our studies in RASFs uncovered a novel crosstalk between the TWEAK/Fn14 receptor and TNF-α signaling, revealing insights into therapy resistance in RA. We identified that Fn14, a unique receptor for TWEAK, is inducible by TWEAK in RASFs. Elevated Fn14 expression was observed in the human synovial tissues and joint homogenates from adjuvant-induced arthritis (AIA) rats. RNA-seq analysis of human RASFs exposed to TNF-α revealed the impact of Fn14 knockdown on TNF-α-induced inflammation. Our in vitro experiments in human RASFs demonstrated that Fn14 siRNA abrogates TNF-α-induced adhesion molecules (PDPN, ICAM-1, VCAM-1, and cadherin-11) and inflammatory chemokines (CCL2, CCL5, CXCL8, and CXCL11). Pharmacological inhibition of Fn14 with L524-0366 antagonist decreased TNF-α-induced phosphorylation of MAPKs- jun N-terminal kinase (JNK) and P38 and of protein kinase C delta type (PKCδ) in RASFs. Co-immunoprecipitation results demonstrated binding between TNF receptor 1 (TNFR1) receptor and Fn14 in RASFs, providing mechanistic insights about the interaction between TNF-α signaling and TWEAK/Fn14 axis. Interestingly, our clinical sample analysis revealed differential TWEAK levels in responders and non-responders to TNFi therapy, suggesting TWEAK as a potential predictive biomarker for treatment outcomes in RA. These findings emphasize the relevance of investigating TWEAK and TNF-α cooperativity in RA. Our findings reveal novel molecular mechanisms by which TNF-α exploits TWEAK/Fn14 non-canonically to exacerbate inflammation in RASFs, potentially paving the way for innovative therapeutic strategies to address the issue of ineffectiveness in TNF-targeted therapies.

THE ROLE OF THE TWEAK/Fn14 AXIS IN THE TNF-α-INDUCED PATHOGENESIS OF RHEUMATOID ARTHRITIS

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