Large-scale computational modelling of the M1 and M2 synovial macrophages in Rheumatoid Arthritis

Abstract

Macrophages play an essential role in rheumatoid arthritis (RA). Depending on their phenotype (M1 or M2), they can play a role in the initiation or resolution of inflammation. The M1/M2 ratio in RA 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 in RA. 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 use a newly developed BMA tool version deployed to a high-performance computing cluster to identify the models steady states. The identified attractors are then validated using gene expression datasets and prior knowledge. We successfully applied our framework to generate and calibrate the first RA M1 and M2 macrophage Boolean models. Using single and double knockout 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 RA.