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

Abstract

Inflammatory hemophagocytes (iHPCs) differentiate from Ly6CHI 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. Ly6CHI 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-{kappa}B, 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 Ly6CHI 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.