| dc.description.abstract | Macrophages are innate immune cells whose main role is the clearance and phagocytosis of microbes and damaged or stressed cells. Also, as antigen-presentingcells, macrophages constitute a bridge between the innate and the adaptive immunity, thus instructing microbe-specific T cell responses. In addition, macrophages can be activated in two different profiles, inflammatory (M1) and anti-inflammatory (M2). Whereas M1 macrophages perform canonical immunological responses, substantially contributing to the inflammatory response, M2 macrophages promote tissue healing and homeostasis recovery following the resolution of the inflammatory challenge. In this project, a macrophage polarization Boolean model developed by our group was updated with two important cascades: proinflammatory TNF-α and anti-inflammatory TGF-β signaling pathways. In addition, eicosanoid biomarkers (proinflammatory and anti-inflammatory lipid mediators) have been linked to M1 and M2 polarization phenotypes. In parallel, the macrophage model was adapted so it represented the macrophage response in the context of acute COVID-19. For this, the polarization model was extended with COVID-19-relevant pathways, including the class I interferon response, the renin-angiotensin system, and the NLRP3 inflammasome activation pathway. Also, the model integrates macrophage intercellular communication with several immune cell types that contribute to the COVID-19 physiopathology, including natural killer cells, CD4+ and CD8+ T-cells, neutrophils, and alveolar epithelial cells. Finally, it was assessed that dexamethasone treatment SARS-CoV-2-infected and uninfected macrophages reduce the spectrum of proinflammatory cytokines triggered by the virus in this cell type. In addition, a combination of dexamethasone with either NFκB or IRF5 inhibitors, or stimulators of key entities from the IL-4 signaling pathway resulted in an improved effect, if compared with treatment only with dexamethasone. Therefore, the outcome of this project is a resource that enables the detailed molecular study of the macrophage polarization process, and can be used as a tool for understanding and predicting the macrophage behavior in the context of COVID-19. In addition, a pipeline for studying dual drug combinations has been defined and applied, thus allowing the testing of potential drug combinations that substantially decrease the SARS-CoV-2-mediated cytokine storm, characteristic of patients with severe COVID-19. | |