Nature https://doi.org/10.1038/s41586-018-0052-z (2018)

Itaconate is a metabolite that arises from the tricarboxylic acid cycle. In Nature, Artyomov and colleagues reveal anti-inflammatory roles for itaconate in macrophages. Itaconate, or its membrane-permeable derivative dimethyl itaconate (DI), induces electrophilic stress in cells by decreasing the effective concentration of intracellular glutathione, thereby decreasing cellular redox buffering capacity. Itaconate and DI activate the integrated stress-response pathway that includes upregulation of the translational regulator ATF3. This scenario suppresses expression of the cytokines IL-6 and IL-12 by interfering with the translation of transcripts encoding IκBζ, a regulator of genes encoding secondary pro-inflammatory response molecules. Notably, in a mouse model of psoriasis, treatment with DI blunts IL-17-stimulated pro-inflammatory responses in keratinocytes and diminishes psoriatic skin lesions.