Dimethyl itaconate, an itaconate derivative, exhibits immunomodulatory effects on neuroinflammation in experimental autoimmune encephalomyelitis

Abstract

Background: Inflammatory stimuli induce immunoresponsive gene 1 (IRG1) expression that in turn catalyzes the production of itaconate from the tricarboxylic acid cycle. Itaconate has recently emerged as a regulator of immune cell functions, especially in macrophages. Studies show that itaconate is required for the activation of anti-inflammatory transcription factor Nrf2 by LPS in mouse and human macrophages, and LPS-activated IRG1-/macrophages that lack endogenous itaconate production exhibit augmented inflammatory responses. Moreover, dimethyl itaconate (DMI), an itaconate derivative, inhibits IL-17-induced IκBς activation in keratinocytes and modulates IL-17-IκBς 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, we investigated whether itaconate possesses an immunomodulatory effect on regulating MG activation and CNS inflammation in animal models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Methods: Chronic C57BL/6 EAE was induced followed by DMI treatment. The effect of DMI on disease severity, bloodbrain barrier (BBB) disruption, MG activation, peripheral Th1/Th17 differentiation, and the CNS infiltration of Th1/Th17 cells in EAE was determined. Primary MG was cultured to study the effect of DMI on MG activation. Relapsing-remitting SJL/J EAE was induced to assess the therapeutic effect of DMI. Results: 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 BBB disruption, inhibited MMP3/MMP9 production, suppressed microglia activation, inhibited peripheral Th1/Th17 differentiation, and repressed the CNS infiltration of Th1 and Th17 cells. Strikingly, DMI also exhibited a therapeutic effect on alleviating severity of relapse in the relapsingremitting SJL/J EAE model.

Exploring the Use of Dimethyl Fumarate as Microglia Modulator for Neurodegenerative Diseases Treatment

“…Indeed, through its immunomodulatory and anti-inflammatory properties, DMI reduces peripheral Th1/Th17 differentiation and CNS infiltration and exerts a protective effect in the EAE mouse model of MS. Moreover, on primary microglia, DMI lowers LPS-induced activation and inflammatory cytokine production [162].…”

Induction of IRG1 following ischemic stroke promotes HO-1 and BDNF expression to alleviate neuroinflammation and restrain ischemic brain injury

“…Moreover, DMI was shown to offer a protection against myocardial and cerebral ischemic/reperfusion injury in animal models (10,11). Finally, DMI was recently reported by our group to suppress neuroin ammation and ameliorate disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (12).…”

“…Presently, the immunomodulatory effects of IRG1/itaconate axis were mainly evaluated in the peripheral in ammatory immune responses. Although we have recently reported that DMI, an itaconate derivative, suppressed neuroin ammation and ameliorated disease severity in the chronic CNS disease, EAE (12), whether IRG1/itaconate axis modulates the acute CNS disease, ischemic stroke, remains unexplored. Hence, in this study we investigated the potential immunomodulatory effects of IRG1 on the alleviation of ischemic brain injury and elucidated the molecular mechanisms underlying the protective effect of IRG1 in ischemic stroke.…”

How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?

“…The DON-mediated ALI resolution also involves the Amphiregulin (Arg) generation. The dimethyl itaconate (DMI, an itaconate derivative) treatment inhibits the pro-inflammatory brain macrophages (microglia), Th1/Th17 differentiation, and neutrophil infiltration in the brain to decrease the neuroinflammation [257]. Thus DMI has the potential to use in severe COVID-19 patients with ALI/ARDS as the lung damage observed involves infiltration and overactivation of macrophages, Th1, and Th17 cells.…”