IRF5 is required for inflammatory hemophagocyte differentiation and disease development in TLR7-mediated Macrophage Activation Syndrome 4643
Year: 2025
Type: article
Abstract: Description Macrophage Activation Syndrome (MAS) is a serious complication of rheumatic disease, characterized by cytopenias and accumulation of hemophagocytes— activated macrophages that phagocytose red blood cells. We previously identified a mouse model (TLR7.1 mice) that develops spontaneous MAS-like disease due to overexpression of and constitutive signaling through the endosomal ssRNA sensor TLR7. TLR7.1 mice develop thrombocytopenia, anemia, and a novel population of hemophagocytes, inflammatory hemophagocytes (iHPCs), which spontaneously differentiate from Ly6CHI monocytes. In humans, SNPs in the transcription factor IRF5 are associated with increased MAS risk. Additionally, IRF5 signaling is critical for inflammatory macrophage development in several inflammatory disease models. Whether monocyte IRF5 is required for MAS development and iHPC differentiation and function is unknown. Here, in TLR7.1 mice, we show that IRF5 signaling is required for iHPC development and hemophagocytosis in a cell-intrinsic manner. We found that myeloid cell IRF5 is required for iHPC differentiation and for some aspects of MAS-like disease in both acute and chronic models of MAS. Using paired RNA-seq and ATAC-seq we are investigating how IRF5 signaling in Ly6CHI monocytes guides iHPC differentiation in spontaneous TLR7-diven MAS. These studies show a critical role of IRF5 in TLR7-driven MAS and in disease-associated hemophagocyte differentiation and function. Funding Sources T32 AI106677; F31AI172078; R01AR076242 Topic Categories Basic Autoimmunity (BA)
Source: The Journal of Immunology
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416451002
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