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Single-cell multi-omics reveals the TNF-α activation threshold for Classical Monocytes by studying healthy donors and rheumatoid arthritis patients

ABSTRACT: Tumor Necrosis Factor Alpha is a known pro-inflammatory cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Anti-cytokine therapies targeting Tumor Necrosis Factor Alpha have greatly succeeded in treating rheumatoid arthritis in many patients. Despite these developments, many of the mechanisms of Tumor Necrosis Factor Alpha action have yet to be uncovered. In this study, we incubated PBMCs from healthy donors and rheumatoid arthritis patients with Tumor Necrosis Factor Alpha and then performed their single-cell multi-omics analysis via BD Rhapsody. We have observed that Classical Monocytes have responded to the Tumor Necrosis Factor Alpha stimulation the most and that there was an activational threshold for such response that was dependent on the TNFR2 protein expression level. The profiling of TNFR2 protein expression level on immune cell populations can be a good predictive factor for the assessment of their activation by Tumor Necrosis Factor Alpha.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289019 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Hayashi2013 - TNF-induced Signaling Dynamics Model (Model A) Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases. This model is described in the article: Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246. Abstract: Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted. Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired. Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Figure 2B, obtained from the simulation of TNFR1 Model A, is highlighted here. This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.

Project description:Hayashi2013 - Extended TNF-induced Signaling with Gene Expression Dynamics (Model B) Tumor necrosis factor (TNF) plays a crucial role in inflammation and is associated with diseases such as rheumatoid arthritis and cancer. While TNF signaling pathways are well studied, targeted regulation of proinflammatory responses remains a challenge. In this study, Hayashi et al., (2013) developed a computational model to simulate TNF-induced activation of MAP kinase (p38), NF-κB, and proinflammatory gene expression in murine fibroblast cells. The model parameters were optimized to fit experimental data, ensuring accurate representation of TNF signaling dynamics. The simulations using in silico knockouts identified receptor-interacting protein 1 (RIP1) as a key regulator of TNF-driven proinflammatory responses. Experimental validation using Necrostatin-1, a RIP1 inhibitor, confirmed these predictions and demonstrated its potential as a therapeutic target for regulating proinflammatory mediators in TNF-driven diseases. This model is described in the article: Hayashi K, Piras V, Tabata S, Tomita M, Selvarajoo K. A systems biology approach to suppress TNF-induced proinflammatory gene expressions. Cell Commun Signal. 2013 Nov 7;11:84. doi: 10.1186/1478-811X-11-84. PMID: 24199619; PMCID: PMC3832246. Abstract: Background: Tumor necrosis factor (TNF) is a widely studied cytokine (ligand) that induces proinflammatory signaling and regulates myriad cellular processes. In major illnesses, such as rheumatoid arthritis and certain cancers, the expression of TNF is elevated. Despite much progress in the field, the targeted regulation of TNF response for therapeutic benefits remains suboptimal. Here, to effectively regulate the proinflammatory response induced by TNF, a systems biology approach was adopted. Results: We developed a computational model to investigate the temporal activations of MAP kinase (p38), nuclear factor (NF)-κB, and the kinetics of 3 groups of genes, defined by early, intermediate and late phases, in murine embryonic fibroblast (MEF) and 3T3 cells. To identify a crucial target that suppresses, and not abolishes, proinflammatory genes, the model was tested in several in silico knock out (KO) conditions. Among the candidate molecules tested, in silico RIP1 KO effectively regulated all groups of proinflammatory genes (early, middle and late). To validate this result, we experimentally inhibited TNF signaling in MEF and 3T3 cells with RIP1 inhibitor, Necrostatin-1 (Nec-1), and investigated 10 genes (Il6, Nfkbia, Jun, Tnfaip3, Ccl7, Vcam1, Cxcl10, Mmp3, Mmp13, Enpp2) belonging to the 3 major groups of upregulated genes. As predicted by the model, all measured genes were significantly impaired. Conclusions: Our results demonstrate that Nec-1 modulates TNF-induced proinflammatory response, and may potentially be used as a therapeutic target for inflammatory diseases such as rheumatoid arthritis and osteoarthritis. Figure S3, obtained from the simulation of TNFR1 Model B, is highlighted here. This model was curated during the Hackathon hosted by BioMed X GmbH in 2024.

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Single-cell multi-omics reveals the TNF-α activation threshold for Classical Monocytes by studying healthy donors and rheumatoid arthritis patients

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