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

Award Number: R01AI195900
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/17/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Role of Fn-14 receptor in TNF-induced inflammation and tissue destruction - 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 administration of Fn14 antagonist (L524- 0366; 10 mg/kg; daily from the disease onset) inhibited collagen antibody-induced arthritis in DBA1/J mice. Based on these novel observations, we hypothesize that TNF-α utilizes the Fn-14 receptor as a non-canonical signaling pathway to induce inflammation. Therefore, in specific aim 1, we plan to determine the molecular mechanisms through which TNF-α utilizes Fn-14 in the synthesis of inflammatory and tissue-destructive mediators in human RASFs and other cells relevant to TNF-α-driven diseases such as IBD and psoriasis. In specific aim 2, we plan to decipher the role of Fn-14 in TNF-α induced function and phenotypic changes in RASFs by using complex multicellular ex-vivo systems, including synovium-on-a-chip model and RA synovial tissue explants. Finally, in specific aim 3, we plan to validate the in vivo efficacy and inhibitory potential of Fn-14- targeted approaches in acute and chronic models of TNF-α-inflammation. The success of these studies will elucidate the role of Fn-14 as a non-canonical signaling receptor of the TNF-α signaling pathway and validate Fn-14 blockade as a potential therapeutic approach for the treatment of RA.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $497,779 )
2026	2026	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Allergy and Infectious Diseases Research	000	1	2/17/2026	NEW	$497,779
														Subtotal = $497,779

Grand Total All Awards = $497,779

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

Award Number: R01AI195900

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/17/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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