# Role of Fn-14 receptor in TNF-induced inflammation and tissue destruction

> **NIH AI R01** · WASHINGTON STATE UNIVERSITY · 2026 · $497,779

## Abstract

PROJECT SUMMARY
Tumor necrosis factor (TNF)-α is a major inflammatory cytokine involved in the pathogenesis of several
autoimmune and inflammatory diseases, including rheumatoid arthritis (RA). Current approaches aim to curb
TNF-α-induced inflammation and tissue damage by treating patients with TNF-α inhibitors (specific antibodies or
soluble receptors). The ineffectiveness of TNF inhibitors in >40% of patients partly indicates that we do not yet
fully understand the underlying signaling mechanisms to effectively target TNF-α. While the use of TNF inhibitors
has provided new insights into human immune and inflammatory systems and the mechanisms involved in
disease processes, adverse events, and the re-emergence of the disease upon cessation of therapy suggest
that other pathways might be involved in re-establishing the disease. Previous studies from our lab using RA
synovial fibroblasts (RASFs) and preclinical models of RA not only shed light on the mechanisms by which TNF-
α utilizes cell surface or cellular proteins to cause progressive inflammation and tissue destruction but also
provided novel pharmacological approaches to suppress TNF-α’s function in RA. In this proposal, our novel
preliminary data show that TNF-α utilizes Fn-14 (fibroblast growth factor-inducible 14), a receptor originally
characterized for mediating TWEAK cytokine signaling. Knockdown of Fn-14 significantly reduced TNF-α-
induced RANTES, MCP-1 and MMP-1 production, and cellular expression of podoplanin and cadherin-11 in
human RASFs. In Fn-14-overexpressing cells, even low TNF-α concentrations synergistically induced
inflammation, suggesting a potential undescribed mechanism exploited by TNF-α to propagate inflammation.
RNA-sequencing analysis revealed >200 differentially expressed genes (DEG) affected by Fn-14 knockdown in
TNF-α stimulated RASFs. Gene set enrichment analysis (GSEA) on the RNA-seq data revealed that IFN-α and
IFN-γ pathway responses were significantly altered. Intraperitoneal

## Key facts

- **NIH application ID:** 11279123
- **Project number:** 1R01AI195900-01
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Salah-uddin  Ahmed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $497,779
- **Award type:** 1
- **Project period:** 2026-02-17T00:00:00 → 2031-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11279123

## Citation

> US National Institutes of Health, RePORTER application 11279123, Role of Fn-14 receptor in TNF-induced inflammation and tissue destruction (1R01AI195900-01). Retrieved via AI Analytics 2026-07-10 from https://api.ai-analytics.org/grant/nih/11279123. Licensed CC0.

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