FOXO3 is involved in the tumor necrosis factor-driven inflammatory response in fibroblast-like synoviocytes

Abstract

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha α (TNFα) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNFα (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNFα and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNFα.

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

“…Thus, for example, early studies perhaps surprisingly reported that miR-155 plays a joint-protective role in RA SFs, having been associated with downregulation of MMP1 and MMP3, mediators that promote SF proliferation and invasion, as well as bone destruction 35, 36, 38, 39, 46 . However, although these studies also indicated that miR-155 did not impact on MMP9 or MMP13 expression or modulate spontaneous or stimulated (TLR ligands/cytokines) TGF β or IL-6 production 41, 47 , more recent work has identified a key role for this miR in driving (spontaneous and TNF α -stimulated) pathogenic responses (proliferation as well as IL-1 β and IL-6 production) via downregulation of its target FOXO3 48–50 , which acts to suppress these functional outcomes in RA-SFs 51 . Thus, given the interactions of miR-155 with multiple TLR and cytokine (IL-1 β , IL-10, IL-17, TNF α , GM-CSF) pathways implicated in regulating arthritogenesis 38, 39 , we further investigated the role of this element in SF pathogenesis and ES-62-mediated protection.…”

The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis

“…In immune cells, FOXO3 activity is critical for maintenance of immune progenitor cell homeostasis (3)(4)(5) and its deficiency in B and T cells leads to their enhanced activity during infection (6). A role of FOXO3 as a powerful immune break was discussed in several studies (7,8). In patients with inflammatory diseases such as rheumatoid arthritis and IBD, genome-wide association studies have shown that individuals with a single nucleotide polymorphism (SNP) in the FOXO3 gene locus leading to lowered FOXO3 expression have a more aggressive disease course (9, 10).…”

Rapid remission of refractory synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome in response to the Janus kinase inhibitor tofacitinib: A case report

“…Different cytokines signal through different JAK combinations; blocking the JAKs can block the action of a number of cytokines directly or indirectly, including γ-chain cytokines, IL-1, IL-6, IL-7, IL-12, IL-15, IL-17, IL-22, IL-23, and TNF-α (Figure 4 ). As a result, JAK inhibitors are emerging therapies that are demonstrating efficacy for the treatment of inflammatory diseases that act through cytokine production[ 17 - 21 ].…”