# ITACONATE AS METABOLIC REGULATOR OF INFLAMMATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $78,750

## Abstract

ABSTRACT
Metabolic rewiring is important regulatory mechanism of the inflammatory activation of immune
cells. In 2013, seminal work by the O'Neill group demonstrated that succinate (TCA cycle
metabolite) acts as a key proinflammatory signal in macrophages, and this work was followed
by intense studies of succinate's functional roles in macrophages and other contexts. Yet,
regulatory mechanisms that control succinate accumulation and utilization still remain unknown.
In our recent work, using a systems biology approach, we dissected the global metabolic
architecture of macrophage activation, corroborated O'Neill's result and showed that upon LPS
stimulation, the TCA cycle becomes disrupted by inactivating isocitrate dehydrogenase (Idh1).
This TCA cycle breakpoint frees citrate to participate in the production of acetyl-CoA, an
important fatty acid synthesis precursor, and in the intracellular production of itaconic acid, a
dicarboxilyc acid metabolite structurally very similar to succinate. Our preliminary data suggest
that high production of itaconate during macrophage activation is functionally critical, as it
provides a natural metabolic regulator to balance the pro-inflammatory function of succinate.
Indeed, by pre-treating macrophages in vitro with itaconate, we observed significant reduction in
the production of NO, IL-6, IL-1β in response to LPS stimulation, as well as dose-dependent
inhibition of IL-1β and IL-18 production during inflammasome activation. We find that itaconate,
like other structural mimetics of succinate (e.g. malonate) is serving as inhibitor of succinate
dehydrogenase (Sdh), an enzyme also known as complex II in the electron transfer chain (ETC)
affecting both ROS production and activity of TCA cycle both in vitro and in vivo. In this grant,
we plan to decipher the regulatory role of itaconate and determine its functional impact on
immune responses in vivo.

## Key facts

- **NIH application ID:** 10151341
- **Project number:** 3R01AI125618-05S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Maksym Artomov
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $78,750
- **Award type:** 3
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151341

## Citation

> US National Institutes of Health, RePORTER application 10151341, ITACONATE AS METABOLIC REGULATOR OF INFLAMMATION (3R01AI125618-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10151341. Licensed CC0.

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