Edited by: Simone Brogi, University of Pisa, Italy
Reviewed by: Xuewei Zhu, Wake Forest School of Medicine, United States; Charles E. McCall, Wake Forest Baptist Medical Center, United States
This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry
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Metabolites have recently been found to be involved in significant biological regulation and changes. Itaconate, an important intermediate metabolite isolated from the tricarboxylic acid cycle, is derived from cis-aconitate decarboxylation mediated by immune response gene 1 in mitochondrial matrix. Itaconate has emerged as a key autocrine regulatory component involved in the development and progression of inflammation and immunity. It could directly modify cysteine sites on functional substrate proteins which related to inflammasome, signal transduction, transcription, and cell death. Itaconate can be a connector among immunity, metabolism, and inflammation, which is of great significance for further understanding the mechanism of cellular immune metabolism. And it could be the potential choice for the treatment of inflammation and immune-related diseases. This study is a systematic review of the potential mechanisms of metabolite associated with different pathology conditions. We briefly summarize the structural characteristics and classical pathways of itaconate and its derivatives, with special emphasis on its promising role in future clinical application, in order to provide theoretical basis for future research and treatment intervention.
In the past decade, how intracellular metabolic changes control immunity and inflammation rose a resurgence of interest in immune metabolism (Kabat and Pearce,
Itaconate was first synthesized by chemical method in 1836 (Baup,
Since itaconate was pushed to the limelight as a key determinant and participated in macrophage stimulation as an important regulatory metabolite. Subsequently, a large amount of researches report that itaconate is a central and determinant component links three fields of immune, metabolism and inflammation together which is of great significance for further understanding mechanism of cellular immune metabolism and drugs development for the treatment of inflammatory and immune-related diseases in the future (Hooftman and O'Neill,
TCA cycle is a complex biological process involving a series of enzyme-catalyzed reactions for Adenosine triphosphate (ATP) production in the mitochondrial matrix (Martínez-Reyes and Chandel,
The Biosynthesis and Metabolism of Itaconate. Itaconate is produced by the decarboxylation of cis-aconitate encoded by aconitate decarboxylase 1. Itaconate inhibits SDH and accumulates Succinate. Pyruvate dehydrogenase complex catalyzes pyruvate into citrate precursor—acetyl-CoA.Itaconate is metabolized into itaconyl-coenzyme A. Itaconyl-coenzyme A inactivates mitochondrial CoA B12 thus inhibits methylmalonyl-CoA mutase and methylmalonyl-CoA conversion.
The lack mechanistic details of itaconate biology and regulatory function has led to the synthesis of several cell-permeable derivatives of itaconate, such as dimethyl itaconate (DI),4-octyl itaconate (4-OI) and ethyl itaconate (4-EI) to imitate the action characteristics of endogenous Itaconate. Thus, this section sets out to perform an introduction of the metabolic, electrophilic, and immunological properties of the itaconate and its three major derivatives reported in the literature to date: Itaconate, DI, 4OI, and 4-EI (
The chemical structures of itaconate and its derivatives.
Chemical formular | C5H6O4 | C7H10O4 | C13H22O4 | C7H10O4 | |
Synthesize year | 1836 | 1906 | 2018 | 1985 | |
Molecular weight (g mol−1) | 130.099 | 158.15 | 242.31 | 158.15 | |
Concentration | 7.5 mM | 0.25 mM | 0.25 mM | 10 mM | |
Electrophilicity | ± | + + | + + | ± | |
Intracellular levels of itaconate | ↑ | – | – | ↑ | |
Immunological properties | Succinate | ↑ | – | – | – |
I-κBζ inhibition | – | + | + | – | |
Pro-IL-1β | – | ↓↓ | ↓ | – | |
Mature IL-1β | ↓ | ↓ | ↓ | ↓ | |
IFN-β | ↓ | ↓↓ | ↓↓ | ↓ |
Itaconate is an α,β-unsaturated dicarboxylic acid (C5H6O4) containing a double bond and two carboxyl groups (Robert and Friebel,
Itaconate derivative dimethyl itaconate (DI) first employed as a chemical experimental material is considered as “powered-up” version of itaconate (RajanBabu et al.,
Esterification on the 1-position of DI is a direct effect on the rapidly intracellular thiols reaction of Nrf2.And to overcome the limitations of DI, Mills designed a new itaconate surrogate, 4-octyl itaconate (4-OI) (Mills et al.,
At present, there are few researches on 4-ethyl itaconate (4-EI), in an article comparing the metabolic, electrophilic, and immunologic profiles of itaconate and its derivatives has mentioned 4-ethyl itaconate (4-EI) (Swain et al.,
The study of itaconate as therapeutic molecules has generated excellent prospects in the pharmaceutical industry due to its low toxicity and high biological activity. None of the above three derivatives can well-simulate the ibona fide targets of itaconate, so there is an urgent need for a more perfect derivative to study the mechanism of itaconate more comprehensively.
At present, there are two kinds of studies on itaconate: Irg1−/− macrophages and the regulatory effect of itaconate derivatives. These two results were complementary and revealed that the regulatory mechanisms of itaconate involved alkylation on Keap1 to activate Nrf2, succinate dehydrogenase inhibition, activating transcription factor 3 (ATF3) induction to inhibit IκBζ activation, down-regulating glycolysis by GAPDH and ALDOA alkylation. The electrophilicity of itaconate and its derivatives are also indispensable in the process of metabolic regulation. Here, we will conclude the classical mechanism of itaconate to clarify its potential targets (
The classical signal pathways of itaconate that have been studied at present. The classical signal pathways of itaconate can be divided into five main types. (1) Itaconate mediated by IRG1 could inhibit due to structural similarity with succinate. (2) Itaconate covalently modify Keap1 cysteine 151 etc.to dissociate the combination of the Keap1-Nrf2, thus promote migration of Nrf2 to cell nuclei. (3) Itaconate increases the levels of ATF3 protein which translocated to the cell nuclei to inhibit IκBζ at the translational level. (4) Itaconate abolish NLRP3-NEK7 connection in a modification termed dicarboxypropylation on C548 of NLRP3 thus block NLRP3-dependent IL-1β release. (5) Itaconate inhibit glycolysis by alkylating cysteine 22 residues on GAPDH, cysteine 73, and 339 on ALDOA. Created with Biorender.
Nrf2 act as a multifunctional and indispensable player in modulating the inflammatory response and oxidative stress (Yang et al.,
The mechanism of inflammation activation is a complex and continuous multi-step process. Except for Nrf2-dependent transcriptional regulation, a unique anti-inflammatory action of itaconate targets on ATF3-IκBζ pathway in a Nrf2-independent manner to mediate the inflammatory response (Bambouskova et al.,
Succinate dehydrogenase(SDH) also called mitochondrial complex II (CII) is an essential component for TCA cycle and cellular respiration via the electron transport chain (Mills et al.,
LPS stimulation changed the immunophenotype of macrophages to pro-inflammatory M1 and up-regulated glycolysis. Macrophages in the state of inflammation activation need to respond rapidly to stimulation by absorbing large amounts of glucose to produce abnormal bioenergy activity through glycolysis (Russell et al.,
Multiple studies have reported that the therapeutic effect of itaconate involved in many diseases, which can be described from the following aspects, including anti-inflammatory, immunomodulatory, antioxidant stress, anti-bacterial, and anti-virus (
Itaconate can be involved in various types of diseases through a variety of regulatory ways.
The participation mechanisms of itaconate in different diseases.
Anti-inflammation | Sepsis | C57(B6) mice |
LPS (Sigma; 2.5 mg/kg;100 ng/ml) |
Keap1/Nrf2-IFN | Mills et al., |
BMDMs(mouse) |
LPS (Sigma, 0.1 μg/mouse; 100 ng/mL) |
Nrf2- HO-1/NQO-1 | Zhang et al., |
||
Whole blood (sepsis patients) |
LPS (Sigma,100 ng/mL; 1 μg/ml) | Itaconate induce immunoparalysis β-glucan reverse immunoparalysis made by itaconate | Li et al., |
||
CAPS | C57(B/6J) mice |
LPS (200 ng/mL) |
NLRP3- IL-1β | Hooftman et al., |
|
PM-Pulmonary inflammation | C57(B/6N,6J)mice |
LPS (Santa;100 ng/ml) |
ACOD1-SDH inhibition | Sun et al., |
|
IPF | C57(B6)mice primary AMs, HLFs(human) |
Itaconate (Sigma, 0.25 mg/kg) | ACOD1-antifibrotic | Ogger et al., |
|
Immunomodulatory | SLE | THP-1 macrophages(human) |
LPS (Sigma; 500 ng/mL) |
Keap1-Nrf2-NF-κB | Tang et al., |
Psoriasis | BMDMs(mouse) |
LPS (Sigma; 100 ng/mL) |
DI-IκBζ- IL-17 | Bambouskova et al., |
|
Multiple sclerosis | C57(B6),SJL/J mice |
LPS (Sigma; 100 ng/mL) |
MMP3, MMP9 inhibition inhibite Th1/Th17 differentiation and infiltration to CNS | Kuo et al., |
|
SAVI | THP-1 cells, PBMCs,HaCat HEK293T, A549 cells(human) | 4-OI (Aarhus University;125 μM, 200 μM) | Nrf2-STING-IFN | Olagnier et al., |
|
Anti-oxidation | Heart | C57(B6, B/6N) mice |
LPS (Sigma; 100 ng/mL) |
SDH inhibition |
Lampropoulou et al., |
Brain | C57(B/6J) mice |
Itaconate (15 mg/kg/min) | SDH inhibition |
Cordes et al., |
|
C57(B6) mice | DMI (Sigma, 20 mg) | Inhibited toxic conversion of microglia | Zhang et al., |
||
Liver | C57 (B/6N, B/6J) mice hepatocytes(human,mouse) |
4-OI (25 mg/kg, 62.5/125 μM) | IRG1-Nrf2- antioxidant | RajanBabu et al., |
|
Kidney | SD Rat |
4-OI (1, 10 mg/kg; 1, 10, 30,1 00 μmol/L) | 4-OI-TGF-β/Smad- NF-κB | Tang et al., |
|
Bone | C57(B6)mice |
LPS (Sigma;10 ng/ml) |
Nrf2—Hrd1- ubiquitination pathway | Sun et al., |
|
Cancer | CAC | C57(B6)mice | DI (10 mg/kg) | Inhibited IL-1β/CCL2 and MDSC Infiltration reduced CAC risk | Wang et al., |
Peritoneal tumors | C57(B6)mice |
/ | Irg1-ROS-MAPK(promote cancer) | Weiss et al., |
|
Anti-bacterial | Tuberculosis |
C57(B6,B/6N)mice |
Itaconate (Sigma, 0.25 mM) | Irg1/NF-κB |
Nair et al., |
Antivirus | COVID-19 SARS-CoV2 HSV-1 |
C57 (B/6N, B/6J) mouse |
4-OI (125 μM, 150 μM) | IRG1- RIPK3 |
Dalglish, |
The role of itaconate and its potential clinical application.
The definition of Sepsis 3.0 is the life-threatening organ dysfunction caused by a host's inappropriate response to infection, emphasizing the imbalance between inflammation and immune homeostasis in sepsis progression (Cecconi et al.,
Cryopyrin-associated periodic syndrome (CAPS) is an inherited autoinflammatory disease with hyperactive nod-like receptor protein 3 (NLRP3) (Ohnishi et al.,
Macrophage-driven lung inflammation is associated with particulate matter (PM) air pollution (McGlade and Landrigan,
Itaconate, kind of inflammation-related endogenous metabolites serve as a novel and inexpensive therapeutic target to control the progression of vascular inflammation disease -abdominal aortic aneurysm (AAA) (Song H. et al.,
In two studies explored about the protective effect of DI to prevent the pathology inflammation of mastitis/endometritis diseases (Zhao et al.,
Immunometabolism, as a burgeoning field has linked intracellular metabolic pathways to immune-mediated inflammation conditions (Diskin et al.,
Multiple sclerosis (MS) is a progressive demyelinating destruction associated with immune-mediated pathogenesis of central nervous system (Faissner et al.,
Systemic lupus erythematosus (SLE) is a common condition characterized by the dysregulation of pro- and anti-inflammatory cytokines (Tsokos et al.,
Rheumatoid arthritis (RA) is a debilitating immune-mediated disease of global prevalence (Weyand and Goronzy,
Stimulator of interferon genes (STING)-associated vasculopathy(SAVI)caused by mutation of TMEM173 gene is a system disruption of inborn innate immune disorders characterized by neonatal onset of autoinflammation diseases (Ahn and Barber,
Ischemia-reperfusion(I/R) injury is a complex pathological condition which drives an imbalance of injurious metabolic processes between oxidative stress and anti-oxidant defense systems (Chamorro et al.,
Cordes et al. found that exogenous itaconate also suppressed SDH and dramatically affected the expression levels of Hmox1, Nqo1, and Gpx1 genes, initiating the transcription of multiple antioxidant and anti-inflammatory protein in cerebral I/R injury model (Cordes et al.,
Oxidative stress is also a major contributor to liver I/R injury apart from cardiac and brain Yi et al. (
Pathological change of vascular endothelial cell injury is the commonest cause of diabetes vasculopathy. Pre-treatment with OI was found have the protection in human umbilical vein endothelial cells (HUVECs) from high glucose (HG)-induced oxidative injury in mimicking Diabetes mellitus (Tang et al.,
Another study has found the renoprotection made by itaconate on renal fibrosis which is recognized as an inevitable pathological progression of all chronic kidney disease (CKD) (Tian et al.,
4-OI affected the suppression of oxidative injury induced by hydrogen peroxide (H2O2) in osteoclast-related diseases. Sun et al. found that the concentration of itaconate was lower in estrogen-deficient mice analyzed by LC-MS assay and the deficiency of Nrf2 was found to induce osteoclastogenesis (Sun et al.,
Recent studies have also found that itaconate plays a vital role in cancer immunometabolism. The anti-cancer property of itaconate has been reported in colitis-associated colorectal cancer (CAC) (Wang et al.,
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the severe bacterial disease in terms of its high mortality and prevalence worldwide (Shin et al.,
Mounting evidence discovered that an unexpected intersection between itaconate and immune activation is intricately linked with antivirus strategies. Zika virus (ZIKV), an emerging human pathogenic virus can cause significant neurologic injury by access the central nervous system (CNS) and has become an increasingly global public health challenge (Zhao et al.,
As every knows, the coronavirus disease 2019 (COVID-19) has rapidly posed an unprecedented global pandemic with high morbidity, mortality, social disruption, and economic instability. But there are limited options on the prevention and treatment of this global health emergency (Dalglish,
Since the key metabolic regulation of itaconate in macrophages was revealed, people have begun to recognize the complex interaction between metabolism, immunity, and inflammation, which provides us a new perspective for the treatment of immune inflammation-related diseases (Kabat and Pearce,
JL and JR designed the main ideas and wrote the article. YD was responsible for literature collection. DG was mainly responsible for language refinement and picture drawing. LY guided the whole process. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.