ATF6α contributes to rheumatoid arthritis by inducing inflammatory cytokine production and apoptosis resistance

Abstract

ObjectiveThe contribution of activating transcription factor 6α (ATF6α) in rheumatoid arthritis (RA) pathogenesis, especially on fibroblast-like synoviocytes (FLSs), has been suggested by its sensitivity to inflammatory stimulus. However, the exact role and therapeutic potential of ATF6α in RA remains to be fully elucidated.MethodsATF6α expression was determined in joint tissues and FLS, and gain-of-function and loss-of-function analyses were applied to evaluate the biological roles of ATF6α in RA FLSs. A murine collagen-induced arthritis (CIA) model, combining both gene deletion of ATF6α and treatment with the ATF6α inhibitor Ceapin-A7, was employed. Joint inflammation, tissue destruction, circulating levels of inflammatory cytokines were assessed in CIA mice. Transcriptome sequencing analysis (RNASeq), molecular biology, and biochemical approaches were performed to identify target genes of ATF6α.ResultsATF6α expression was significantly increased in synovium of RA patients and in synovium of mice subjected to CIA. ATF6α silencing or inhibition repressed RA FLSs viability and cytokine production but induced the apoptosis. CIA-model mice with ATF6α deficiency displayed decreased arthritic progression, leading to profound reductions in clinical and proinflammatory markers in the joints. Pharmacological treatment of mice with Ceapin-A7 reduced arthritis severity in CIA models. RNA-sequencing of wild-type and knockdown of ATF6α in RA FLSs revealed a transcriptional program that promotes inflammation and suppresses apoptosis, and subsequent experiments identified Baculoviral IAP Repeat Containing 3 (BIRC3) as the direct target for ATF6α.ConclusionThis study highlights the pathogenic role of ATF6α-BIRC3 axis in RA and identifies a novel pathway for new therapies against RA.

Cell-Specific Gene Networks and Drivers in Rheumatoid Arthritis Synovial Tissues

“…Syn we show the 10 most significant pathways for each cell type. As expected, well-established RA pathways are evident across multiple cell types, such as TNF [49], IRF [50] and ATF6 [51], along with pathways associated with osteoclast differentiation [52] and T helper (Th) cell differentiation [53]. Our analysis also identified less commonly documented pathways in the context of RA, such as those associated with RUNX1, found in monocytes and fibroblasts, and HOX, predominantly in fibroblasts and T cells.…”

Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats

“…Map3k1 regulates numerous intracellular signaling pathways involved in inflammation and apoptosis (49). Birc3 activates the NF-kB and MAPK pathways (50). Collectively, the significant improvement in LT-AMR by anti-C5 antibodies was at least substantially attributable to the attenuation of the inflammatory cycle.…”

Endoplasmic Reticulum Stress in Systemic Lupus Erythematosus and Lupus Nephritis: Potential Therapeutic Target

“…Interestingly, guanabenz protected mice from CpG oligonucleotide-dependent cytokine shock and alleviated autoimmune symptom severity in a mouse model of pristane-induced lupus [ 34 ]. Ceapin-A7, as an ATF6 α inhibitor, alleviates alleviated collagen-induced arthritis and bone erosion in a mouse model by suppressing the inflammatory cytokine production [ 144 ]. However, the potential applications of ATF6 α inhibitors in SLE and LN have yet to be revealed.…”