# IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2022 · $577,613

## Abstract

Project Summary
Macrophage Activation Syndrome (MAS) is an acute complication associated with rheumatic diseases. MAS is
most commonly seen in patients with systemic juvenile idiopathic arthritis (sJIA) and pediatric lupus, however
MAS can develop after viral infections, such as with EBV. MAS involves the accumulation of activated
macrophages in the bone marrow, spleen and liver that have phagocytosed red blood cells (RBCs) and
leukocytes. MAS is associated with increased inflammatory cytokines, cytopenias such as anemia and
thrombocytopenia, and high serum ferritin. In the absence of treatment, MAS can be fatal, and most death in
sJIA are due to MAS. Thus, understanding the mechanisms underlying MAS in rheumatic and inflammatory
diseases is important for the development of new methods of therapeutic intervention. To identify novel
pathways contributing to MAS, we focused on the identification of pathologic macrophages in a mouse model
of MAS. As the phagocytosis of RBCs, platelets, and leukocytes can be a major contributor to the acute
cytopenia seen in MAS, we reasoned that specialized phagocytes may be involved in disease pathogenesis.
We found that chronic signaling via endosomal TLR7 and TLR9 directly induced differentiation of a novel
macrophage population termed inflammatory hemophagocytes (iHPC), which differentiated from Ly6Chi
monocytes. Transgenic overexpression of TLR7 not only caused the development of iHPC, but also caused a
lethal MAS-like disease that could be rescued by iHPC depletion. MAS secondary to sJIA and to viral infection
is associated with variants in the gene encoding IRF5, a transcription factor activated downstream of TLR
signaling in monocytes and macrophages. Our preliminary data show that IRF5 also participates in TLR7-
induced iHPC differentiation both in vitro and in vivo, and that IRF5 is hyper-activated in iHPC in our mouse
model of TLR7-induced MAS. The premise of this application is that IRF5 signaling downstream of endosomal
TLR7 and TLR9 is a critical component of iHPC differentiation and MAS. In this proposal we will 1) Test the
hypothesis that IRF5 is required for iHPC differentiation and disease in a mouse model of TLR7-driven MAS, 2)
Determine the mechanisms by which IRF5 participates in iHPC differentiation, and 3) Test the hypothesis that
IRF5 is constitutively activated in iHPC and/or monocytes from sJIA patients with MAS. Successful completion
of these studies will determine whether IRF5 is a viable therapeutic target for MAS in sJIA and other
autoimmune diseases.

## Key facts

- **NIH application ID:** 10454915
- **Project number:** 5R01AR076242-04
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Betsy J Barnes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,613
- **Award type:** 5
- **Project period:** 2019-07-24 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454915

## Citation

> US National Institutes of Health, RePORTER application 10454915, IRF5 and Macrophage Activation Syndrome in systemic Juvenile Idiopathic Arthritis (5R01AR076242-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10454915. Licensed CC0.

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