4-Octyl-Itaconate and Dimethyl Fumarate Inhibit COX2 Expression and Prostaglandin Production in Macrophages

Abstract

Prostaglandins (PGs) are important proinflammatory lipid mediators, the significance of which is highlighted by the widespread and efficacious use of non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammation. 4-Octyl itaconate (4-OI), a derivative of the Krebs cycle-derived metabolite itaconate, has recently garnered much interest as an anti-inflammatory agent. Here we show that 4-OI limits PG production in macrophages stimulated with the Toll-like receptor 1/2 (TLR1/2) ligand Pam3CSK4. This decrease in PG secretion is due to a robust suppression of COX2 expression by 4-OI, with both mRNA and protein levels decreased. Dimethyl fumarate (DMF), a fumarate derivative used in the treatment of multiple sclerosis (MS), with properties similar to itaconate, replicated the phenotype observed with 4-OI. We also demonstrate that the decrease in COX2 expression and inhibition of downstream prostaglandin production occurs in an NRF2-independent manner. Our findings provide a new insight into the potential of 4-OI as an anti-inflammatory agent and also identifies a novel anti-inflammatory function of DMF.

Nrf2 activation reprograms macrophage intermediary metabolism and suppresses the type I interferon response

“…Of note, 4-OI was less able to suppress type I IFN response proteins, such as IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), and other IFN associated effector proteins in Nrf2-KO macrophages ( Figures 4 D and S6 D). 4-OI was also found to decrease prostaglandin transporters in a Nrf2-independent manner ( Figures 4 D and 4E), which is consistent with a recent report demonstrating inhibition of prostaglandin synthesis and release in macrophages ( Diskin et al., 2021 ). This highlights an important role for Nrf2 in mediating certain, but not all aspects of the immunomodulatory capabilities of 4-OI.…”

Innate metabolic responses against viral infections

“…When aerobic glycolysis is increased during immune activation, GAPDH can disengage binding to the 3′ untranslated region of mRNAs encoding IFN-γ, causing its translation 85 . In addition to controlling enzyme activities in various metabolic pathways, metabolites also possess anti-inflammatory 86,87 and inflammatory 75 properties and regulate viral replication 60,88,89…”

Itaconate, Arginine, and Gamma-Aminobutyric Acid: A Host Metabolite Triad Protective Against Mycobacterial Infection

“…Future studies are needed to address how Nrf2 signaling is associated with itaconate-mediated protection against mycobacterial infection. Moreover, either 4-octyl itaconate or dimethyl itaconate exerts anti-inflammatory effects and inhibits aerobic glycolysis, thus controlling pathologies related to excessive inflammation (4,46,52,53). Therefore these itaconate derivatives may enhance antimycobacterial responses by controlling pathologic inflammation and immunometabolism during infection.…”