Sepsis is an inflammatory disease characterized by dysregulation of inflammation. Macrophage-mediated inflammation has been implicated in the pathophysiology of sepsis. Itaconate is a metabolite produced in activated macrophages which has anti-inflammatory activities. In the present study, we investigated the potential effects of a cell-permeable itaconate derivative dimethyl itaconate on inflammation in sepsis. We established a lipopolysaccharide (LPS)-induced septic mouse model and administered dimethyl itaconate to the septic mice. The survival rate, serum level of pro-inflammatory cytokines, and lung pathology were evaluated. We also administered dimethyl itaconate to LPS-treated bone marrow-derived macrophages (BMDMs), and measured the cytokine production and Nrf2 expression. We also evaluated the effects of dimethyl itaconate on Nrf2-deficient mice. Administration of dimethyl itaconate enhanced survival rate, decreased serum level of TNF-α and IL-6, and ameliorated lung injury in septic mice. Dimethyl itaconate also suppressed LPS-induced production of TNF-α, IL-6, and NOS2 in BMDMs. Dimethyl itaconate activated Nrf2 and promoted the expression of Nrf2 and its downstream factor HO-1 and NQO-1. The regulatory activities of dimethyl itaconate on inflammatory cytokine production, mouse survival rate were abolished in septic Nrf2 mice. Dimethyl itaconate suppressed the inflammatory responses of macrophages in sepsis.
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