Dimethyl itaconate is a membrane-permeable derivative of the immunoregulatory metabolite itaconate. Itaconate is one of the most highly induced metabolites produced when activated macrophages undergo metabolic remodeling. Itaconate acts as a major physiological regulator of metabolic switching and effector functions of inflammatory macrophages. Itaconate and dimethyl itaconate inhibit production of IL-6 and IL-12 (secondary transcriptional response), but not TNF (a primary transcriptional response) following Toll-like receptor stimulation [4
Itaconate has been found to promote an electrophilic stress response (i.e.
a rapid adaptive defense response) [1
]. An electrophilic stress response involves various mechanisms, including the nuclear translocation of the redox-sensitive transcription factor Nrf2 (nuclear factor E2-related factor 2), which senses electrophilic and oxidative stresses and protects against cellular damage via
Kelch-like ECH-associated protein 1 (Keap1) [2-3
]. Both itaconate and dimethyl itaconate induce Nrf2-dependent and -independent responses, the Nrf2-independent response being that which involves regulation of IκBζ