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-1? in response to LPS stimulation, as well as dose-dependent inhibition of IL-1? 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.

Public Health Relevance

Metabolic rewiring is important regulatory mechanism controlling activation of the immune cells. Succinate is one of the major metabolic regulators of macrophage activation, playing distinct proinflammatory role. Our preliminary data suggest that high production of itaconate during macrophage activation is functionally critical, as it provides a natural, structural mimetic metabolic regulator to balance the pro-inflammatory function of succinate. In this grant, we plan to decipher the regulatory role of itaconate and determine its functional impact on immune responses in vivo using newly generated Irg1-/- and Irg1fl/fl mice that lack itaconate producing enzyme.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI125618-01A1
Application #
9310797
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Jiang, Chao
Project Start
2017-08-01
Project End
2022-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130