A Mechanistic Cellular Atlas of the Rheumatic Joint

Abstract

Rheumatoid Arthritis (RA) is an autoimmune disease of unknown aetiology involving complex interactions between environmental and genetic factors. Its pathogenesis is suspected to arise from intricate interplays between signalling, gene regulation and metabolism, leading to synovial inflammation, bone erosion and cartilage destruction in the patients’ joints. In addition, the resident synoviocytes of macrophage and fibroblast types can interact with innate and adaptive immune cells and contribute to the disease’s debilitating symptoms. Therefore, a detailed, mechanistic mapping of the molecular pathways and cellular crosstalks is essential to understand the complex biological processes and different disease manifestations. In this regard, we present the RA-Atlas, an SBGN-standardized, interactive, manually curated representation of existing knowledge related to the onset and progression of RA. This state-of-the-art RA-Atlas includes an updated version of the global RA-map covering relevant metabolic pathways and cell-specific molecular interaction maps for CD4+ Th1 cells, fibroblasts, and M1 and M2 macrophages. The molecular interaction maps were built using information extracted from published literature and pathway databases and enriched using omic data. The RA-Atlas is freely accessible on the webserver MINERVA (https://ramap.uni.lu/minerva/), allowing easy navigation using semantic zoom, cell-specific or experimental data overlay, gene set enrichment analysis, pathway export or drug query.

Metabolic Reprogramming in Rheumatoid Arthritis Synovial Fibroblasts: a Hybrid Modeling Approach

“…This work presents the construction of the first RASF-specific asynchronous Boolean model combining signaling, gene regulation, and metabolism. To obtain this model, the state-of-the-art RA-map V2 (Zerrouk et al, 2022) was used along with the map-to-model framework proposed by Aghamiri et al, 2020. The model was inferred based on RASF-specific pathways and components according to scientific literature. Additional biocuration ensured high cellular-specificity for RASFs.…”

“…The copyright holder for this preprint (which this version posted July 21, 2022. ; https://doi.org/10. 1101/2022…”

“…The cellular-specificity of the model was evaluated by comparing its components' cellular origin to eight different sample-type specific lists provided in the RA-Atlas publication (Zerrouk et al, 2022). They are specific to RASFs, synovial tissue, synovial fluid, blood and serum components, peripheral blood mononuclear cells, chondrocytes, and macrophages.…”

“…As fragmented as it may be, a collection of the knowledge in terms of extra-and intra-cellular signaling along with gene regulation pathways involved in RASFs' metabolic reprogramming would be beneficial. Efforts have already been made in this direction with the publication of the first RA-map (Singh et al, 2020), followed by the RA-Atlas (Zerrouk et al, 2022).…”

“…It was obtained by combining a cell-specific asynchronous Boolean network covering gene regulation and signaling machinery with a global constraint-based metabolic network. This hybrid The RA-map V2, included in the RA-Atlas (Zerrouk et al, 2022), provided the starting point for this work. It illustrates the central signaling, gene regulation and metabolic pathways (i.e., glycolysis, PPP, TCA and OXPHOS), along with molecular mechanisms and phenotypes involved in RA's pathogenesis.…”