# Itaconate mediated control of inflammatory hemophagocyte accumulation

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2024 · $44,154

## Abstract

The goal of this proposal is to investigate the mechanisms through which the enzyme IRG1 and its
metabolic product itaconate deplete inflammatory hemophagocytes to prevent severe anemia. Maintaining the
balance between the production and clearance of red blood cells (RBCs) is important for proper oxygenation of
the tissue and prevention of anemia. During inflammation, this balance often goes askew as the clearance of
RBCs by macrophages in a process known as hemophagocytosis in the spleen and liver increases. The
enhanced hemophagocytosis observed during inflammation is mediated primarily by monocytes that have
differentiated into macrophages with markedly enhanced hemophagocytic capacity as opposed to tissue
macrophages. Our collaborators in the Hamerman lab have recently found that Ly6Chi monocytes differentiate
into a unique population of specialized hemophagocytes termed inflammatory hemophagocytes (iHPCs) in
mouse models of severe malarial anemia and lupus like disease driven by transgenic TLR7 overexpression.
During blood stage Plasmodium yoelii-17XNL infection, iHPCs have been shown to contribute to severe
malarial anemia. Currently, the mechanisms that regulate the monocyte to iHPC transition remain unknown.
 The metabolite itaconate, which is produced by the enzyme IRG1, has been shown to alter
inflammatory signaling by activating the anti-inflammatory transcription factor NRF2 and inhibiting succinate
dehydrogenase (SDH) activity to induce metabolic changes that limit the production of reactive oxygen species
(ROS). Surprisingly, we found that Irg1 is highly upregulated in Plasmodium infected Ly6Chi monocytes and
iHPCs, indicative of metabolic regulation of iHPCs. Preliminary data from our lab generated using mouse
models of both Plasmodium infection and TLR7 stimulation to induce iHPCs have revealed a cell intrinsic role
of Irg1 in depleting iHPCs in the circulation and the spleen. To better understand the mechanism underlying
itaconate mediated depletion of iHPCs, we isolated WT and Irg1-/- Ly6Chi monocytes and observed reduced
cell death in the Irg1-/- monocytes compared to the WT, suggesting that itaconate is inducing death in the
precursor population to regulate the accumulation of iHPCs. Our lab has previously shown that activation of the
RIP kinases, key components of necroptotic signaling, induce Irg1 expression. Furthermore, itaconate has
been shown to itaconylate RIPK3 to enhance necroptosis. Interestingly, knocking out RIPK3 enhanced iHPC
accumulation, implicating the necroptotic pathway as one way in which iHPCs are regulated. Based on our
findings, the goal of this proposal is to elucidate the interactions between IRG1/itaconate and RIPK3 that
promote necroptosis in Ly6Chi monocytes (Aim 1) and to assess how inhibition of necroptosis in vivo alters the
accumulation of iHPCs and anemia severity (Aim 2). With the support and training from this fellowship, I will be
able to continue advancing my knowledge of immunological tech...

## Key facts

- **NIH application ID:** 10895175
- **Project number:** 1F31AI178955-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Katrina Lichauco
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,154
- **Award type:** 1
- **Project period:** 2024-03-16 → 2025-06-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895175

## Citation

> US National Institutes of Health, RePORTER application 10895175, Itaconate mediated control of inflammatory hemophagocyte accumulation (1F31AI178955-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10895175. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*