# Defining signals contributing to inflammatory hemophagocyte differentiation in TLR7 mediated Macrophage Activation Syndrome

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2022 · $43,045

## Abstract

Project Summary/Abstract
 The goal of this research is to investigate the development of inflammatory macrophages and disease in
Macrophage Activation Syndrome (MAS). MAS is a serious and potentially fatal complication of rheumatic
disease or viral infection. MAS is characterized by the development of cytopenias, including anemia and
thromobocytopenia, and accumulation of hemophagocytes— activated macrophages that phagocytose red
blood cells (RBCs). I will investigate spontaneous MAS-like disease in a mouse model of Systemic Lupus
Erythematosus. In the TLR7.1 model, the overexpression of and constitutively active signaling through the
endosomal single-stranded RNA sensor Toll-like receptor 7 (TLR7) drives chronic inflammation and subsequent
MAS disease. TLR7.1 mice develop thrombocytopenia, anemia, and a novel population of hemophagocytes,
inflammatory hemophagocytes (iHPCs), that spontaneously differentiate from Ly6Chi monocytes. Further, in this
model, the development of anemia is positively correlated with iHPC phagocytosis of RBCs indicating that iHPC
activity may be driving disease.
 In humans, SNPs in the gene encoding the transcription factor interferon regulatory factor 5 (IRF5) are
associated with MAS development. IRF5 signaling is critical for the development of inflammatory macrophages
in the context several inflammatory diseases. Previous work in our lab showed that IRF5 ablation in vivo
ameliorates iHPC differentiation downstream of acute TLR7 signaling. However, in the context of in vivo TLR7-
driven MAS, the role of IRF5 signaling in iHPC production and in MAS disease is unclear. In preliminary data, I
show in TLR7.1 mice that signaling through IRF5 is critical for iHPC development, iHPC RBC phagocytosis, and
anemia and thrombocytopenia indicative of MAS disease development. Based on these findings, the goal of my
proposal is to determine the role of IRF5 signaling, specifically in Ly6Chi monocytes, in TLR7- driven iHPC
differentiation and MAS disease (AIM 1), and to determine what other signals synergize with TLR7 to drive iHPC
differentiation and MAS disease, with a specific focus on heme and type I interferons (AIM 2). Overall, completion
of the proposed research along with my additional training described here will allow me to pursue my goals of
becoming an independent investigator and faculty member with a focus on education.

## Key facts

- **NIH application ID:** 10534552
- **Project number:** 1F31AI172078-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Natalie K Thulin
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,045
- **Award type:** 1
- **Project period:** 2022-09-16 → 2025-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10534552

## Citation

> US National Institutes of Health, RePORTER application 10534552, Defining signals contributing to inflammatory hemophagocyte differentiation in TLR7 mediated Macrophage Activation Syndrome (1F31AI172078-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10534552. Licensed CC0.

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