Dimethyl Itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis
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ORIGINAL ARTICLE
Dimethyl Itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis Sheng Zhang,1 Yalou Jiao,2 Chao Li,1 Xiao Liang,1 Huiqin Jia,1 Zhelong Nie,1 and Yanwei Zhang 1,3
(Received June 18, 2020; accepted September 28, 2020)
Abstract—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. KEY WORDS: dimethyl itaconate; inflammation; macrophages; sepsis.
1
Department of Emergency, Xingtai People’s Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China 2 Department of Reproductive Medicine, Xingtai People’s Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China 3 To whom correspondence should be addressed at Department of Emergency, Xingtai People’s Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China. E-mail: [email protected] Abbreviations LPS, Lipopolysaccharides; BMDMs, Bone marrow– derived macrophages; OI, Octyl itaconate; Nrf2, Nuclear factor-erythroid 2–related factor 2; PBS, Phosphate-buffered saline; FBS, Fetal bovine serum; H&E, Hematoxylin and eosin
INTRODUCTION Sepsis, which is characterized by dysregulation of inflammation, is an inflammatory immune response triggered by an infection [1]. Due to the high morbidity and mortality, sepsis affects around 30 million people and causes around 7 million deaths every year, causing great economic burden [2].
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Zhang, Jiao, Li, Liang, Jia, Nie, and Zhang The core mechanism underlying sepsis development is immune dysfunction. Excessive inflammatory responses have been identified to be associate
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