Metabolite itaconate in host immunoregulation and defense

Area of Science:

• Immunology
• Metabolic pathways
• Cellular metabolism

Background:

• Immune cell function and differentiation are significantly influenced by metabolic states.
• Modulating immune cell metabolism offers a strategy to control host immune responses.
• Itaconate, a tricarboxylic acid (TCA) cycle intermediate, is synthesized by cis-aconitate decarboxylase (encoded by IRG1) in mitochondria.

Purpose of the Study:

• To comprehensively review the role of IRG1/itaconate and its derivatives in regulating macrophage metabolism and functions.
• To elucidate the connection between itaconate, macrophage metabolism, oxidative stress, and immune response.
• To explore the potential therapeutic applications of itaconate in inflammatory diseases and cancer.

Main Methods:

• Literature review of studies on IRG1, itaconate, and macrophage biology.
• Analysis of signaling pathways influenced by itaconate, including Keap1-Nrf2-ARE, ATF3-IκBζ, and STING.
• Examination of itaconate's impact on inflammatory diseases and cancer development.

Main Results:

• IRG1 expression is upregulated in macrophages upon proinflammatory stimulation.
• Itaconate inhibits succinate dehydrogenase, altering macrophage metabolic status.
• Itaconate modulates inflammatory and antioxidant responses via multiple signaling pathways.

Conclusions:

• Itaconate acts as a crucial link between macrophage metabolism, oxidative stress, and immune function.
• Understanding IRG1/itaconate pathways offers potential for novel therapeutic strategies.
• Itaconate's role in inflammation and cancer warrants further investigation for clinical applications.