Itaconát
Itaconate
- Highly polar molecule
- Cannot easily pass through cell membranes
- Must be imported into the cytoplasm to exert anti-inflammatory effects
- itaconate can be transferred from mitochondria into salmonella-containing vacuoles
- Through organelle interactions driven by the IRG1-Rab32-BLOC3 system
- Exerting antibacterial functions
Exogenous itaconate was not absorbed into cells
- RAW264.7 macrophages, A549 lung adenocarcinoma cells, and brown adipocytes
- Accumulated significant amounts of itaconate
- Immune effects resulting from this accumulation were not taken into consideration
- Supplemented exogenous itaconate to the culture of resting mouse macrophages
- itaconate was able to efficiently penetrate into macrophages
- Neither itaconate nor 4-EI induced significant expression of Nrf2-driven electrophilic stress markers Nqo1 and Hmox1
- itaconate itself
- Did not induce Nrf2 protein expression in the absence of inflammatory/oxidative factors
- Prolonged LPS stimulation
- itaconate and 4-EI are relatively less electrophilic
- Natural itaconate increased the release of
- IFN-beta
Membrane-permeable itaconate derivatives
- None of the itaconate derivatives
- Produced significant intracellular amounts of itaconate
- Non-derived natural itaconate
- Accumulated in unstimulated and activated macrophages
Dimethyl itaconate (DI)
- DI not metabolized into itaconate in mice bone marrow-derived macrophages
4-octyl itaconate (4-OI)
- 4-OI had a similar thiol reactivity that was far lower than that of DI
- Suitable cell-permeable itaconate surrogate
- Hydrolyzed to itaconate by esterases in mouse myoblast C2C12 cells and LPS-activated macrophages
- 4-OI may be more suitable for experiments as a simulated derivative of itaconate.
- no itaconate production was observed after the application of 1 mM DI and 4-OI in RAW264.7 cells
- In resting and LPS-activated macrophages DI and 4-OI
- Strongly induced the expression of the Nrf2-driven electrophilic stress markers Nqo1 and Hmox1
4-monoethyl itaconate (4-EI)
- Neither itaconate nor 4-EI induced significant expression of Nrf2-driven electrophilic stress markers Nqo1 and Hmox1
- DI and 4-OI are strongly electrophilic compounds
- DI and 4-OI treatment limited the release of IFN-beta in macrophages after LPS stimulation
IRG1-/- macrophages
- Released fewer IFN-beta than wild-type macrophages
- RNA sequencing analysis
- Downstream gene expression of type I IFN signaling
- Significantly impaired in IRG1-/- macrophages
- Immunomodulator rather than a purely immunosuppressive metabolite
Citraconate
- Derivative isomers of itaconate
- Ability to suppress glycolysis
- Less effective than itaconate at inhibiting succinate dehydrogenase, TCA cycle, or oxidative phosphorylation
- Citraconate and mesaconate, like itaconate
- Could restrain the production of proinflammatory cytokines
- Protecting against sepsis
- Lowering influenza replication in mouse models
Mesaconate
- Derivative isomers of itaconate
- Immunomodulatory effects in macrophages
- Ability to suppress glycolysis
- Less effective than itaconate at inhibiting succinate dehydrogenase, TCA cycle, or oxidative phosphorylation
- Citraconate and mesaconate, like itaconate
- Could restrain the production of proinflammatory cytokines
- Protecting against sepsis
- Lowering influenza replication in mouse models
Dimethyl fumarate
- Reduce Itaconate levels
Itaconate
- Accumulates in macrophages
- Because of the disturbance in the Krebs cycle
- Derived from cis-aconitate
- By the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1)
Roles include
- Inhibition of succinate dehydrogenase
- Controls levels of succinate - multiple roles in inflammation
- Inhibition of glycolysis at multiple levels ( limit inflammation)
- Activation of the antiinflammatory transcription factors Nrf2 and ATF3
- Inhibition of the NLRP3 inflammasome
- Itaconate and its derivatives have antiinflammatory effects in
- Preclinical models of sepsis,
- Viral infections,
- Psoriasis,
- Gout,
- Ischemia/reperfusion injury,
- Pulmonary fibrosis,
- itaconate antibacterial to:
- Salmonella enterica
- Mycobacterium tuberculosis (Mtb)
- These bacteria use carbon sources produced by the glyoxylate shunt to survive
- Itaconate inhibits this glyoxylate shunt
- Blocking a key enzyme isocitrate lyase
- Itaconate stops Mtb from using carbon sources from cholesterol degradation
- By inhibiting Mtb mediated detoxification of propionic acid
- Alkylate cystine residues
- Changes to protein structure and binding
- Exogenous itaconate treatment of bone-marrow-derived macrophages
- Upregulates IFN-beta
- itaconate and its derivative 4-Octyl itaconate, (4-OI)
- Inhibits NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation
- Preventing the secretion of IL-1beta implicated in COVID-19
- Reduces other inflammatory cytokines such as IL-6 and IL-10
- Antiviral against Zika virus (ZIKV) in murine models
- itaconate inhibits succinate dehydrogenase
- Causing succinate accumulation
- Driving an antiviral metabolic state in neurons
- Via reduced TCA cycle metabolism
- Reduced oxygen consumption rate
- IRG1 knock-out mice
- Have higher levels of ZIKV replication
- IRG1 mediates
- Antiviral state in primary cortical neurons against West Nile Virus (WNV)
- itaconate could have antiviral properties against
- ZIKV, WNV and possibly SARS-CoV-2
4-OI, a derivative of itaconate
- Activate nuclear factor-erythroid factor 2-related factor 2 (NRF2)
- Via the alkylation of Kelch Like ECH Associated Protein 1 (KEAP1)
