Large-scale computational modelling of the M1 and M2 synovial macrophages in rheumatoid arthritis

Abstract

Macrophages play an essential role in rheumatoid arthritis. Depending on their phenotype (M1 or M2), they can play a role in the initiation or resolution of inflammation. The M1/M2 ratio in rheumatoid arthritis is higher than in healthy controls. Despite this, no treatment targeting specifically macrophages is currently used in clinics. Thus, devising strategies to selectively deplete proinflammatory macrophages and promote anti-inflammatory macrophages could be a promising therapeutic approach. State-of-the-art molecular interaction maps of M1 and M2 macrophages in rheumatoid arthritis are available and represent a dense source of knowledge; however, these maps remain limited by their static nature. Discrete dynamic modelling can be employed to study the emergent behaviours of these systems. Nevertheless, handling such large-scale models is challenging. Due to their massive size, it is computationally demanding to identify biologically relevant states in a cell- and disease-specific context. In this work, we developed an efficient computational framework that converts molecular interaction maps into Boolean models using the CaSQ tool. Next, we used a newly developed version of the BMA tool deployed to a high-performance computing cluster to identify the models’ steady states. The identified attractors are then validated using gene expression data sets and prior knowledge. We successfully applied our framework to generate and calibrate the M1 and M2 macrophage Boolean models for rheumatoid arthritis. Using KO simulations, we identified NFkB, JAK1/JAK2, and ERK1/Notch1 as potential targets that could selectively suppress proinflammatory macrophages and GSK3B as a promising target that could promote anti-inflammatory macrophages in rheumatoid arthritis.

Crosstalk between Inflammation and Atherosclerosis in Rheumatoid Arthritis and Systemic Lupus Erythematosus: Is There a Common Basis?

“…In recent years, research has also been conducted in the field of drug delivery, such as bioactive nanoparticles and macrophage-derived macrovesicle-coated nanoparticles, to overcome the side effects and limitations of traditional systemic drugs. However, no specific macrophage-targeted treatments are currently in clinical use [ 68 ].…”

Immunoregulatory role of platelet derivatives in the macrophage-mediated immune response

“…Therefore, they exhibit a pro-inflammatory phenotype with antimicrobial and antitumoral activities ( 18 , 20 , 23 ). Moreover, M1 macrophages are involved in matrix degradation by direct and indirect production of matrix metalloproteinases (MMPs) and a variety of antifibrotic cytokines such as CXCL10 ( 18 , 24 , 25 ). Conversely, M2 macrophages are activated by Th2 cytokines including IL-4 and IL-13 and express high level of scavenger proteins such as mannose receptor (CD206) ( 18 , 26 , 27 ).…”