Cloning and analysis of gene regulation of a novel LPS-inducible cDNA

Itaconate is an important immunomodulatory metabolite that negatively regulates the inflammatory response and cytokine production.

“Since 2016, several key studies have uncovered a role for itaconate as a crucial anti-inflammatory metabolite that negatively regulates the inflammatory response and cytokine production50,59–61, as shown in Figure 3.”

1EI can inhibit IκBξ.

“1EI (an activated Michael acceptor) could also inhibit IκBξ”

The selective inhibition of IL-6 by DI is mediated through inhibition of IκBξ.

“an effect shown to be mediated through inhibition of IκBξ the major transcription factor governing secondary transcriptional responses to TLR activation60.”

DI induces electrophilic stress and Nrf2 in macrophages via depletion of intracellular GSH to form a DI-GSH adduct.

“Bambouskova and colleagues (2018) demonstrated that DI could induce electrophilic stress and Nrf2 in macrophages via depletion of intracellular GSH to form a DI-GSH adduct”

No differences in IκBξ levels are observed between Irg1-/- and wildtype macrophages stimulated with LPS.

“no differences were observed in IκBξ levels between Irg1-/- and wildtype macrophages stimulated with LPS60.”

4EI cannot inhibit IκBξ unless GSH synthesis is inhibited by BSO.

“4EI (which has similar reactivity to endogenous itaconate) could not inhibit IκBξ unless GSH synthesis was inhibited by buthionine sulfoximine (BSO)60.”

LPS-induced Nrf2 stabilisation is decreased in Irg1-deficient BMDMs.

“Bambouskova and colleagues (2018) who demonstrated a decrease in LPS-induced Nrf2 stabilisation in Irg1-deficient BMDMs”

Inhibition of IκBξ by DI is mediated by activation of ATF3 and occurs at the level of Nfkbiz translation, as assessed by eIF2α phosphorylation, in a Nrf2-independent manner.

“inhibition of IκBξ by DI was shown to be mediated by activation of the transcription factor ATF3 and occur at the level of Nfkbiz translation, as assessed by eIF2α phosphorylation, in a Nrf2-independent manner60.”

DI selectively inhibits LPS-induced IL-6 while TNF-α levels remain unaffected.

“DI is reported to selectively inhibit LPS-induced IL-6 while TNF-α levels remain unaffected”

Endogenous itaconate stabilizes Nrf2.

“confirming that endogenous itaconate stabilizes Nrf260.”

High levels of succinate or 2-HG inhibit α-KGDDs, including PHDs, TET DNA demethylases, and JMJDs.

“High levels of succinate or 2-HG inhibit α-KGDDs. These include the PHDs, the TET DNA demethylases, and the JMJDs154-156”

In vivo administration of DI ameliorates skin pathology in a mouse model of psoriasis.

“The therapeutic potential of DI was also demonstrated as in vivo administration of DI resulted in an amelioration of skin pathology in a mouse model of psoriasis, a disease also currently treated by the related electrophile DMF60,65.”

Itaconate primarily acts as a protective, anti-inflammatory metabolite.

“The generation of itaconate from the Krebs Cycle intermediate cis-aconitate contrasts with most other metabolite signals emanating from mitochondria, in that it primarily acts as a protective, anti-inflammatory metabolite55,59,60.”