Chronic exposure to TNF reprograms cell signaling pathways in fibroblast-like synoviocytes by establishing long-term inflammatory memory

Abstract

Fibroblast-like synoviocytes (FLS) play a critical role in the pathogenesis of rheumatoid arthritis (RA). Chronic inflammation induces transcriptomic and epigenetic modifications that imparts a persistent catabolic phenotype to the FLS, despite their dissociation from the inflammatory environment. We analyzed high throughput gene expression and chromatin accessibility data from human and mouse FLS from our and other studies available on public repositories, with the goal of identifying the persistently reprogrammed signaling pathways driven by chronic inflammation. We found that the gene expression changes induced by short-term tumor necrosis factor-alpha (TNF) treatment were largely sustained in the FLS exposed to chronic inflammation. These changes that included both activation and repression of gene expression, were accompanied by the remodeling of chromatin accessibility. The sustained activated genes (SAGs) included established pro-inflammatory signaling components known to act at multiple levels of NF-kappaB, STAT and AP-1 signaling cascades. Interestingly, the sustained repressed genes (SRGs) included critical mediators and targets of the BMP signaling pathway. We thus identified sustained repression of BMP signaling as a unique constituent of the long-term inflammatory memory induced by chronic inflammation. We postulate that simultaneous targeting of these activated and repressed signaling pathways may be necessary to combat RA persistence.

SOX4 and RELA Function as Transcriptional Partners to Regulate the Expression of TNF- Responsive Genes in Fibroblast-Like Synoviocytes

“…Among the various signaling pathways that drive FLS transformation, NF-kappaB (NF-kB) signaling downstream of Tumor necrosis factor (TNF)-alpha plays a critical role in joint degeneration by driving a wide range of cellular and molecular changes leading to synovial hyperplasia, cartilage degeneration and bone loss (3,4). Importantly, the genomic and transcriptomic responses of the FLS from TNF-driven arthritis mouse model are largely comparable to the responses FLS from human RA patients (5,6). RELA/p65 is the transcription factor that mediates gene expression changes induced by the canonical NF-kB signaling pathway (7).…”

Skin innate immune response against fungal infections and the potential role of trained immunity

“…The authors observed that the sustained activated genes are NF‐kappaB, STAT and AP‐1 signalling cascades. The sustained repressed genes included critical mediators and targets of the bone morphogenetic protein (BMP) signalling pathway 94 …”

“…In addition to pathogens and other exogenous immunogenic compounds, recent research has shown that TI can also be induced indirectly through the production of specific cytokines. 94,95 Tumour necrosis factor alpha (TNFα) therapy results in longterm transcriptomic and epigenetic reprogramming in fibroblast-like synoviocytes that contribute to chronic inflammation in rheumatoid arthritis. The authors observed that the sustained activated genes are NF-kappaB, STAT and AP-1 signalling cascades.…”

“…The sustained repressed genes included critical mediators and targets of the bone morphogenetic protein (BMP) signalling pathway. 94 β-glucan is capable of inducing TI in stem and haematopoietic stem progenitor cells (HSPCs), even though these cells lack the dectin-1 receptor. Mitroulis et al 95 Since IL-1β is capable of epigenetically reprogramming monocytes in a similar way to β-glucan, the induction of TI via IL-1β may be involved in the pathogenesis of sporotrichosis and linked to severe tissue destruction by S. brasiliensis.…”

Role and mechanism of fibroblast-activated protein-α expression on the surface of fibroblast-like synoviocytes in rheumatoid arthritis

“…For example, T cell chemokines can stimulate FLS activation, maintain the inflammatory phenotype of the cells, and use FLSs as antigenpresenting cells, leading to T cell activation and proliferation that act synergistically with the abnormal immune system to further drive inflammation (30,31). However, the persistent inflammatory secretion of FLSs disappears upon removal of these cellular stimuli, while some of the cell surface biomarkers remain activated in the legacy (32,33). Persistently high expression of surface proteins has a memorability, which makes FLSs more sensitive to inflammatory stimuli.…”