IRF5 is required for iHPC differentiation in a mouse model of TLR7-driven macrophage activation syndrome and inhibition of IRF5 activity rescues from disease severity 3604

Description Abstract In Macrophage Activation Syndrome (MAS), severe macrophage and T cell activation results in systemic inflammation and organ dysfunction. Using a TLR7-overexpressing mouse model (TLR7.1), we observed a MAS-like condition characterized by thrombocytopenia and anemia in part due to the generation of a unique population of hemophagocytes called inflammatory hemophagocytes (iHPCs). We found that loss or inhibition of IRF5 function in vivo protects from disease onset and/or severity of MAS. Methods We generated TLR7.1/Irf5+/- or TLR7.1Irf5-/- mice and utilized the IRF5 inhibitor (N5-1) in the TLR7.1 MAS model to examine the requirement of IRF5 in the differentiation and function of iHPCs. iHPC generation, hemophagocytosis and IRF5 activation were assessed by FC and IFC throughout disease progression. N5-1 was administered in a preclinical and therapeutic dosing regimen. Results Results demonstrate that N5-1 partially inhibits iHPC generation, prevents hemophagocytosis, and alleviates MAS in TLR7.1 mice. Additionally, Irf5 deficiency in TLR7.1 mice nearly fully rescues the MAS phenotype. Conclusions These findings highlight the pivotal role of IRF5 in the development of inflammatory hemophagocytes (iHPCs) and the process of hemophagocytosis. Further exploration of IRF5 inhibitors in preclinical models, with a focus on their safety and efficacy, could provide a promising therapeutic strategy for the treatment or prevention of Macrophage Activation Syndrome (MAS).