Abstract
4-Octyl itaconate (OI) is a novel anti-inflammatory metabolite that exerts protective effects in many various disease models. However, its function in autoimmune hepatitis- (AIH-) associated hepatic injury has not been investigated. In this study, we successfully used concanavalin A (Con A) to establish an AIH-associated liver injury model. Furthermore, we investigated the effect of OI in Con A-induced liver injury and found that OI mitigated Con A-induced histopathological damage. OI administration reduced serum levels of alanine transaminase and aspartate transaminase in Con A-treated mice and attenuated the infiltration of macrophages induced by Con A. Moreover, OI effectively inhibited the expression of proinflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and IL-1β induced by Con A. Furthermore, OI decreased hepatocyte apoptosis and malondialdehyde levels and increased the reduced glutathione/oxidized glutathione ratio in the Con A-induced liver injury model. In addition, we found that OI inhibited Con A-induced hepatocyte apoptosis in vitro, while Nrf2 deletion eliminated this effect. Furthermore, we administrated the Nrf2 inhibitor ML385 in OI+Con A-treated mice and found that ML385 eliminated the protective effect of OI in vivo. In addition, OI inhibited Con A-induced activation of nuclear factor-kappa B (NF-𝜅B) and the expression of proinflammatory cytokines in macrophages. Therefore, OI protected mice from Con A-induced liver damage and may be associated with Nrf2 activation and NF-𝜅B inhibition. Finally, our study revealed that OI inhibited TNF-α, or supernatants from Con A-treated RAW264.7 cells induced hepatocyte apoptosis. In conclusion, our study indicated that OI alleviated Con A-induced hepatic damage by reducing inflammatory response, oxidative stress, and apoptosis.
Highlights
Acute hepatitis is a common and serious health issue worldwide [1]
Our results revealed that Octyl itaconate (OI) treatment ameliorated concanavalin A (Con A)-induced liver injury by reducing inflammatory response, oxidative stress, and apoptosis, and the underlying mechanism was associated with nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling activation and NF-κB pathway inhibition
We have previously confirmed that Con A significantly increased reactive oxygen species (ROS) levels in hepatocytes and promoted liver damage [16]. cPARP is validated as reliable marker for apoptosis [43]
Summary
Acute hepatitis is a common and serious health issue worldwide [1]. Multiple pathogenic factors including toxins, organisms, and autoimmune diseases can lead to hepatic injury and probably incur fulminant hepatitis [2–5]. The pathology of numerous hepatic diseases is involved in inflammatory response, oxidative stress, and hepatocytes death [6–8]. Multiple physiological metabolites in macrophages have exhibited immunoregulation properties and exerted protective effects in various disease models. Itaconate, produced from citrate, is one of the most abundant metabolites in activated macrophages [17] It exerts protective effects in several inflammation-associated diseases by inhibiting excessive inflammation [18]. We previously found that Nrf activation mitigated carbon tetrachloride-induced hepatic injury by inhibiting oxidative stress and inflammation [24]. We investigated the effect of OI on a Con A-induced AIH model and found that OI protected mice from Con A-induced liver injury. OI administration in Con A-induced AIH reduced hepatocyte death, inflammation, and oxidative stress. Our current study found that OI might be a potential therapeutic strategy for AIH
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