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Dimethyl Itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis

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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.

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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

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Authors and Affiliations

  1. Department of Emergency, Xingtai People’s Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China

    Sheng Zhang, Chao Li, Xiao Liang, Huiqin Jia, Zhelong Nie & Yanwei Zhang

  2. Department of Reproductive Medicine, Xingtai People’s Hospital of Hebei Province, No. 16 Hongxing Street, Xingtai, 054031, Hebei, China

    Yalou Jiao

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  1. Sheng Zhang
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  2. Yalou Jiao
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Correspondence to Yanwei Zhang.

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Mice were kept in a specific pathogen-free environment in accordance with protocols approved by the ethics committee of Xingtai People’s Hospital of Hebei Province.

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The authors declare that they have no conflict of interest.

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Zhang, S., Jiao, Y., Li, C. et al. Dimethyl Itaconate Alleviates the Inflammatory Responses of Macrophages in Sepsis. Inflammation 44, 549–557 (2021). https://doi.org/10.1007/s10753-020-01352-4

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  • DOI: https://doi.org/10.1007/s10753-020-01352-4

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