The RNA binding protein Arid5a is an activator of TNF signaling in rheumatoid arthritis

TL;DR

Arid5a, an RNA binding protein, is found to be elevated in rheumatoid arthritis and contributes to disease progression by enhancing TNF signaling.

Contribution

Arid5a is identified as a new signaling intermediate downstream of TNF in rheumatoid arthritis.

Findings

ARID5A mRNA is elevated in human RA tissues and reduced by anti-TNF therapy.

Arid5a–/– mice are resistant to collagen-induced arthritis with reduced Th17 cells in synovial tissue.

Abstract

Rheumatoid arthritis (RA) is characterized by joint inflammation and bone erosion. Understanding cytokine pathways, particularly those targeting TNF, is crucial for understanding pathology and advancing treatment development. Arid5a is a noncanonical RNA binding protein (RBP) that augments inflammation through stabilizing proinflammatory mRNAs and enhancing protein translation. We examined published datasets for ARID5A in human RA blood, T cells, and synovial tissues. A stromal cell line, epithelial cells, and primary synovial fibroblasts were used to assess the effect of TNF on Arid5a expression, localization, and function. To determine how TNF induces Arid5a, WT or Traf2–/– stromal cells were treated with NIK or IKK inhibitors. To evaluate the necessity of Arid5a in arthritis progression, Arid5a–/– mice were subjected to collagen-induced arthritis. ARID5A was elevated in patients with RA and reduced by anti-TNF therapy. TNF upregulated Arid5a through the NF-κB1/TRAF2 pathway, causing cytoplasmic relocalization. Arid5a stabilized proinflammatory transcripts and enhanced expression of chemokines that drive RA. Arid5a–/– mice were resistant to collagen-induced arthritis correlating with reduced Th17 cells in synovial tissue. Thus, Arid5a serves as a newly recognized signaling intermediate downstream of TNF that is elevated in human RA and drives pathology in murine CIA, potentially positioning this RBP as a possible therapeutic target.

The cytokine TNF is a major driver of rheumatoid arthritis. We have identified a new mediator of TNF signaling through a noncanonical RNA binding protein, Arid5a. ARID5A mRNA is elevated in human RA tissues, and Arid5a-/- mice are resistant to collagen induced arthritis.

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