Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2

Heinz, Alexander; Nonnenmacher, Yannic; Henne, Antonia; Khalil, Michelle‐Amirah; Bejkollari, Ketlin; Dostert, Catherine; Hosseini, Shirin; Goldmann, Oliver; He, Wei; Palorini, Roberta; Verschueren, Charlène; Körte, Martin; Chiaradonna, Ferdinando; Medina, Eva; Brenner, Dirk; Hiller, Karsten

doi:10.1016/j.bbadis.2022.166530

Cited by 13 publications

(9 citation statements)

References 31 publications

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“…48 IRG1, which encodes itaconate, is considered one break point of the TCA cycle. 49 Itaconate can inhibit the activity of succinate dehydrogenase in mitochondria and thereby inhibits the mitochondrial TCA cycle. IRG1 drives metabolite reprogramming of macrophages, and the fate of macrophages is thus obviously changed.…”

Section: Discussionmentioning

confidence: 99%

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IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway

Zhou,

Yu,

Bai

et al. 2024

Cancer Science

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Intrahepatic cholangiocarcinoma (ICC) is a highly malignant and aggressive cancer whose incidence and mortality continue to increase, whereas its prognosis remains dismal. Tumor‐associated macrophages (TAMs) promote malignant progression and immune microenvironment remodeling through direct contact and secreted mediators. Targeting TAMs has emerged as a promising strategy for ICC treatment. Here, we revealed the potential regulatory function of immune responsive gene 1 (IRG1) in macrophage polarization. We found that IRG1 expression remained at a low level in M2 macrophages. IRG1 overexpression can restrain macrophages from polarizing to the M2 type, which results in inhibition of the proliferation, invasion, and migration of ICC, whereas IRG1 knockdown exerts the opposite effects. Mechanistically, IRG1 inhibited the tumor‐promoting chemokine CCL18 and thus suppressed ICC progression by regulating STAT3 phosphorylation. The intervention of IRG1 expression in TAMs may serve as a potential therapeutic target for delaying ICC progression.

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Section: Discussionmentioning

confidence: 99%

“…Therefore, macrophages can adopt different survival modes and show corresponding functional differences 48 . IRG1, which encodes itaconate, is considered one break point of the TCA cycle 49 . Itaconate can inhibit the activity of succinate dehydrogenase in mitochondria and thereby inhibits the mitochondrial TCA cycle.…”

Section: Discussionmentioning

confidence: 99%

IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway

Zhou,

Yu,

Bai

et al. 2024

Cancer Science

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“…The accumulation of itaconate has been recognized as characteristic of inflammation and the killing activity of M1 macrophages ( 41 ). In M1 macrophages, itaconate is produced in mitochondria through aconitase decarboxylase 1 (ACOD1) ( 42 ) ( Figure 3A ). It has been shown that itaconate enhances innate antibacterial immunity ( 43 ).…”

Section: Cellular Metabolism-mediated Macrophage Polarizationmentioning

confidence: 99%

The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization

An,

Tan,

Yang

et al. 2024

Front. Immunol.

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Macrophages polarized into distinct phenotypes play vital roles in inflammatory diseases by clearing pathogens, promoting tissue repair, and maintaining homeostasis. Metabolism serves as a fundamental driver in regulating macrophage polarization, and understanding the interplay between macrophage metabolism and polarization is crucial for unraveling the mechanisms underlying inflammatory diseases. The intricate network of cellular signaling pathway plays a pivotal role in modulating macrophage metabolism, and growing evidence indicates that the Hippo pathway emerges as a central player in network of cellular metabolism signaling. This review aims to explore the impact of macrophage metabolism on polarization and summarize the cell signaling pathways that regulate macrophage metabolism in diseases. Specifically, we highlight the pivotal role of the Hippo pathway as a key regulator of cellular metabolism and reveal its potential relationship with metabolism in macrophage polarization.

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“…In Mycobacterium tuberculosis (Mtb) infection, the metabolite glutamine drives M1 macrophage responses via immunometabolic remodeling in which the biosynthetic precursor ITA is generated ( 25 ). In turn, ITA functions as a feedback inhibitory regulator by TCA-cycle reprogramming in macrophages ( 26 ). That is, ITA inhibits isocitrate dehydrogenase 2 (IDH2), thereby altering the mitochondrial NADP+/NADPH ratio and inhibiting SDH ( 26 ).…”

Section: Immune Regulation Via the Irg1-ita Pathwa...mentioning

confidence: 99%

“…In turn, ITA functions as a feedback inhibitory regulator by TCA-cycle reprogramming in macrophages ( 26 ). That is, ITA inhibits isocitrate dehydrogenase 2 (IDH2), thereby altering the mitochondrial NADP+/NADPH ratio and inhibiting SDH ( 26 ). In addition, interleukin (IL)-33-mediated metabolic rewiring in macrophages upregulates ITA production, and ITA promotes the GATA3-mediated polarization of alternatively activated macrophages, thereby contributing to tissue repair and the resolution of inflammation ( 27 ).…”

Section: Immune Regulation Via the Irg1-ita Pathwa...mentioning

confidence: 99%

Itaconate family-based host-directed therapeutics for infections

et al. 2023

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Itaconate is a crucial anti-infective and anti-inflammatory immunometabolite that accumulates upon disruption of the Krebs cycle in effector macrophages undergoing inflammatory stress. Esterified derivatives of itaconate (4-octyl itaconate and dimethyl itaconate) and its isomers (mesaconate and citraconate) are promising candidate drugs for inflammation and infection. Several itaconate family members participate in host defense, immune and metabolic modulation, and amelioration of infection, although opposite effects have also been reported. However, the precise mechanisms by which itaconate and its family members exert its effects are not fully understood. In addition, contradictory results in different experimental settings and a lack of clinical data make it difficult to draw definitive conclusions about the therapeutic potential of itaconate. Here we review how the immune response gene 1-itaconate pathway is activated during infection and its role in host defense and pathogenesis in a context-dependent manner. Certain pathogens can use itaconate to establish infections. Finally, we briefly discuss the major mechanisms by which itaconate family members exert antimicrobial effects. To thoroughly comprehend how itaconate exerts its anti-inflammatory and antimicrobial effects, additional research on the actual mechanism of action is necessary. This review examines the current state of itaconate research in infection and identifies the key challenges and opportunities for future research in this field.

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Itaconate controls its own synthesis via feedback-inhibition of reverse TCA cycle activity at IDH2

Cited by 13 publications

References 31 publications

IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway

IRG1 restrains M2 macrophage polarization and suppresses intrahepatic cholangiocarcinoma progression via the CCL18/STAT3 pathway

The potential role of Hippo pathway regulates cellular metabolism via signaling crosstalk in disease-induced macrophage polarization

Itaconate family-based host-directed therapeutics for infections

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