Myeloid IRF5 is required for TLR7-driven inflammatory hemophagocyte differentiation and Macrophage Activation Syndrome
- 1Benaroya Research Institute
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.
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BibTeX
@misc{thulin2026myeloid,
title = {{Myeloid IRF5 is required for TLR7-driven inflammatory hemophagocyte differentiation and Macrophage Activation Syndrome}},
author = {N. K. Thulin and A. Lu and S. L. Orozco and A. Y. Y. Huang and L. P. Nguyen and G. Mishra and R. Savan and W. Clapp and J. Ray and J. Hamerman and B. J. Barnes},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.18.745337},
url = {https://www.biorxiv.org/content/10.64898/2026.08.18.745337v2},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Myeloid IRF5 is required for TLR7-driven inflammatory hemophagocyte differentiation and Macrophage Activation Syndrome
AU - N. K. Thulin
AU - A. Lu
AU - S. L. Orozco
AU - A. Y. Y. Huang
AU - L. P. Nguyen
AU - G. Mishra
AU - R. Savan
AU - W. Clapp
AU - J. Ray
AU - J. Hamerman
AU - B. J. Barnes
PY - 2026
DA - 2026/08/18
PB - bioRxiv
DO - 10.64898/2026.08.18.745337
UR - https://www.biorxiv.org/content/10.64898/2026.08.18.745337v2
AB - 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.
SN - 2692-8205
ER -