Work

Myeloid IRF5 is required for TLR7-driven inflammatory hemophagocyte differentiation and Macrophage Activation Syndrome

Year: 2026

Type: preprint

Abstract: ABSTRACT Inflammatory hemophagocytes (iHPCs) differentiate from Ly6C HI monocytes, phagocytose red blood cells, and promote anemia and thrombocytopenia in a model of TLR7-driven macrophage activation syndrome (MAS), a life-threatening disorder. We identify IRF5 as a required and pharmacologically targetable driver of iHPC differentiation and MAS pathogenesis. Ly6C HI monocyte-to-iHPC differentiation in TLR7.1 mice involved extensive transcriptome and chromatin remodeling. Gene programs gained in iHPCs were enriched for genes near accessible IRF5-binding regions that also carried NF-κB, ETS, and AP-1 motifs, suggesting collaborative regulation. IRF5 was required in vitro for TLR7-induced upregulation of a subset of these genes. Cell-intrinsic IRF5 expression was required for iHPC differentiation but dispensable for TLR7.1 Ly6C HI monocytes and their transcriptional programs. Constitutive and myeloid-specific Irf5 deletion, as well as a small-molecule IRF5 inhibitor, reduced iHPCs and ameliorated MAS and lupus features. IRF5 is therefore a broad regulator of iHPC differentiation and a tractable target in TLR7-driven inflammation. SUMMARY In TLR7-driven MAS, specialized monocyte-derived inflammatory hemophagocytes promote disease. Thulin, Lu et al. show that myeloid cell IRF5 is required for iHPC differentiation and MAS, and that IRF5 likely partners with other transcription factors, including NF-κB, to shape iHPCs programs.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.08.18.745337