Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function,
cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is
itaconate, which is derived from cis-
aconitate by the
enzyme cis-
aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on
itaconate's emergence as a key immunometabolite with diverse roles in immunity and
inflammation. These roles include inhibition of
succinate dehydrogenase (which controls levels of
succinate, a metabolite with multiple roles in
inflammation), inhibition of glycolysis at multiple levels (which will limit
inflammation), activation of the antiinflammatory
transcription factors Nrf2 and ATF3, and inhibition of the NLRP3
inflammasome.
Itaconate and its derivatives have antiinflammatory effects in preclinical models of
sepsis,
viral infections,
psoriasis,
gout,
ischemia/reperfusion injury, and
pulmonary fibrosis, pointing to possible
itaconate-based
therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and
inflammation.