Dimethyl Itaconate, an Itaconate Derivative, Exhibits Immunomodulatory Effects on Neuroinflammation in Experimental Autoimmune Encephalomyelitis

Abstract

Abstract Itaconate has recently emerged as a regulator of immune cell function. Studies show that itaconate is required for the activation of anti-inflammatory transcription factor Nrf2 by LPS in macrophages. Moreover, dimethyl itaconate (DMI), an itaconate derivative, has been shown to inhibit IL-17-induced IκBζ activation in keratinocytes and modulate IL-17-IκBζ pathway-mediated skin inflammation in an animal model of psoriasis. Currently, the effect of itaconate on regulating macrophage functions and peripheral inflammatory immune responses is well established. However, its effect on microglia (MG) and CNS inflammatory immune responses remains unexplored. Thus, in this study we investigated whether itaconate possesses an immunomodulatory effect on regulating MG activation and CNS inflammation in experimental autoimmune encephalomyelitis (EAE). Chronic C57BL/6 EAE and relapsing-remitting SJL/J EAE were induced to assess the therapeutic effect of DMI. Our results show DMI ameliorated disease severity in the chronic C57BL/6 EAE model. Further analysis of the cellular and molecular mechanisms revealed that DMI mitigated blood-brain barrier disruption, inhibited MMP3 and MMP9 production, suppressed microglia activation, and repressed CNS infiltration of Th1 and Th17 cells. Strikingly, DMI also exhibited a therapeutic effect on lessening severity of relapse in the relapsing-remitting SJL/J EAE model. In conclusion, we demonstrate for the first time that DMI suppressed neuroinflammation and ameliorated disease severity in EAE through multiple cellular and molecular mechanisms, and our findings suggest that DMI can be developed as a novel therapeutic agent for the treatment of EAE through its anti-inflammatory properties.