Multi-omics profiling of collagen-induced arthritis mouse model reveals early metabolic dysregulation via SIRT1 axis

Abstract

Rheumatoid arthritis (RA) is characterized by joint infiltration of immune cells and synovial inflammation which leads to progressive disability. Current treatments improve the disease outcome, but the unmet medical need is still high. New discoveries over the last decade have revealed the major impact of cellular metabolism on immune cell functions. So far, a comprehensive understanding of metabolic changes during disease development, especially in the diseased microenvironment, is still limited. Therefore, we studied the longitudinal metabolic changes during the development of murine arthritis by integrating metabolomics and transcriptomics data. We identified an early change in macrophage pathways which was accompanied by oxidative stress, a drop in NAD+ level and induction of glucose transporters. We discovered inhibition of SIRT1, a NAD-dependent histone deacetylase and confirmed its dysregulation in human macrophages and synovial tissues of RA patients. Mining this database should enable the discovery of novel metabolic targets and therapy opportunities in RA.

Unveiling the Nexus: Cellular Metabolomics Unravels the Impact of Estrogen on Nicotinamide Metabolism in Mitigating Rheumatoid Arthritis Pathogenesis

“…Thereby, we further evaluated the effect of this metabolic pathway on RA through E2 induction. The report shows that 1-methyl nicotinamide (1-MNA) is a central metabolite that is synthesized by N-methylation of nicotinamide [50], known to show a significant reduction in RA plasma [51]. Our data depicted its significant upregulation, implying that E2 stimulates nicotinamide biosynthesis.…”

Modeling causal signal propagation in multi-omic factor space with COSMOS

“…Most of the current efforts to interpret the results of such analyses have focused on characterizing known meta-data variables (e.g. clinical variables) that may correlate with factors, or using pathway ontologies to interpret the feature weights of factors [23][24][25][26][27][28][29][30][31][32][33]68,69 . However, there are many more types of domain knowledge that can potentially be used to interpret feature weights of factors beyond pathway ontologies, such as prior knowledge in the form of footprints and signed-directed networks can help to provide interpretable insights from factor weights.…”

“…While very useful, the resulting multi-omic factors and their associated weights are purely data-driven. They can be further analyzed to provide molecular mechanistic context, and this is typically done by pathway enrichment analysis and/or association with clinical features [23][24][25][26][27][28][29][30][31][32][33] .…”

Regulation of autophagy by circular RNAs in rheumatoid arthritis: Potential targets of action

“…Therefore, SIRT1 activity can be a key determinant of biological and clinical outcomes 72 . SIRT1 expression is dysregulated in human macrophages and synovial tissues of RA patients and is associated with proinflammatory cytokine production 74,75 . The involvement of circRNA‐targeted miRNAs in disease pathogenesis is also associated with SIRT1 activity 76 .…”

“…72 SIRT1 expression is dysregulated in human macrophages and synovial tissues of RA patients and is associated with proinflammatory cytokine production. 74,75 The involvement of circRNA-targeted miRNAs in disease pathogenesis is also associated with SIRT1 activity. 76 In the circRNA-targeted miR-132/ NF-κB axis, which inhibits cell inflammation in the human RA-FLS MH7A cell line, circ SIRT1 acts as a competing endogenous RNA in a closed-loop structure to competitively bind with miR-132, activating the Sirt1 signal pathways.…”