# The Role of Macrophage Dynamics in Atherosclerosis Analyzed Using a Petri Net-Based Model
## 4 Conclusions  
The study investigates the complex relationship between cholesterol homeostasis, macrophage dynamics, and atherosclerosis using a classical Petri net model based on biological and medical literature. The model suggests that inhibiting M-CSF significantly affects the formation of atherosclerotic plaques by altering macrophage behavior and inflammatory responses, while disturbances in cholesterol homeostasis continue to lead to lipid accumulation. This is supported by research indicating M-CSF's pivotal role in macrophage activation, foam cell creation, and chronic inflammation, which are essential for plaque development and instability [44; 46; 49]. As a result, future therapeutic strategies that aim to target M-CSF and its associated cytokines are proposed to mitigate inflammatory conditions, thus potentially decreasing the risk of adverse events related to atherosclerosis [49]. The inhibition of IL-23 also shows its role in inflammation and atherosclerosis, suggesting therapeutic targets by modulating the IL-23/IL-17 axis. It is also associated with increased mortality in carotid artery stenosis and is detected in atherosclerotic plaques, emphasizing its role in promoting atherosclerosis through TH17 cell activation in mice [70]. Although IL-23 is investigated for atherosclerosis treatment, meta-analyses suggest that IL-23 blockers such as ustkeinumab could not improve or worsen cardiovascular outcomes in patients with psoriasis. This highlights the complex role of IL-23, but the primary focus on psoriasis in these studies limits conclusions about its impact on atherosclerosis, making its direct effects uncertain [71; 72]. The model also points to the potential of the CXCL12/ CXCR4 pathway in the treatment of atherosclerosis by inhibiting HSPCs' mobilization and plaque formation. This alignswith recent literature, suggesting that the CXCL12/CXCR4 axis performs more complex functions than previously understood. CXCL12 and its receptors are now considered potential therapeutic targets and biomarkers for atherosclerosis [73; 74]. It also emphasizes that macrophage polarization towards anti-inflammatory states could markedly reduce plaque development. This aligns with current literature, which suggests that, since macrophage polarization plays a role at various stages, targeting it could be a key strategy for atherosclerosis management. Balancing macrophage subtypes and promoting anti-inflammatory transformations might offer effective prevention and treatment options [48; 75; 76; 77]. The development of atherosclerosis is complex and cannot be fully halted by lipid-lowering therapies. These insights align with current research, highlight strategies such as reducing M1 polarization for therapeutic benefits, and underscore the importance of macrophage regulation and cholesterol pathways in atherosclerosis, suggesting avenues for future research and novel treatment approaches. Furthermore, our comprehensive mathematical model, which surpasses earlier suggestions [13; 14; 15; 16; 17; 18; 19; 20; 21; 22], covers a broad spectrum of processes related to the interplay between cholesterol balance, macrophage behavior, and the development of atherosclerosis. This enhanced predictive capacity of the model not only confirms its value in identifying therapeutic targets but also facilitates the simulation of various clinical scenarios to explore new treatment strategies and responses to potential medications. Conceptualization, A.R., D.F. and P.F. ; model development, D.F. ; system analysis, A.R., D.F. and P.F. ; biological conclusions, A.R. and D.F. ; writing--original draft preparation, A.R., D.F. and P.F. ; funding acquisition, D.F. and P.F. All authors have read and agreed to the published version of the manuscript. This work was partially supported by the National Science Centre (Poland) grant No. 2012/07/B/ST6/01537, by statutory funds of Poznan University of Technology and by statutory funds of Poznan University of Medical Sciences. Not applicable. Data are contained within the article.