Int J Biol Sci 2022; 18(16):6189-6209. doi:10.7150/ijbs.74456 This issue Cite

Research Paper

4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis

Peng Zhang1#, Yaxin Wang2#, Wengchang Yang1, Yuping Yin1, Chengguo Li1, Xianxiong Ma1, Liang Shi1, Ruidong Li1✉, Kaixiong Tao1✉

1. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
2. Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
#These authors contributed equally to this work.

Citation:
Zhang P, Wang Y, Yang W, Yin Y, Li C, Ma X, Shi L, Li R, Tao K. 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis. Int J Biol Sci 2022; 18(16):6189-6209. doi:10.7150/ijbs.74456. https://www.ijbs.com/v18p6189.htm
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Abstract

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Introduction: Sepsis is a major global health challenge with high mortality rates and no effective treatment. Recent studies have suggested that sepsis may be associated with immune system dysfunction. Itaconate may exert anti-inflammatory effects via Nrf2 signaling. Although Nrf2 regulates oxidative/exogenous stress responses and inhibits inflammatory responses, the mechanism via which Nrf2 regulates immune checkpoints in sepsis remains unclear.

Objectives: This study aimed to investigate the role of the Nrf2 signaling pathway in sepsis immunosuppression injury by exploring Nrf2 target genes in inflammatory macrophages in a mouse model of sepsis.

Methods: We evaluated the effects of 4-octyl itaconate (OI) on pro-inflammatory and anti-inflammatory cytokines in a mouse model of sepsis and RAW264.7 cells. In addition, we investigated if OI could inhibit LPS-induced oxidative stress by activating Nrf2 signaling in vitro and in vivo.

Results: OI reduced the release of pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines, thereby inhibiting inflammation. OI increased glutathione synthase (GSS) expression by activating the Nrf2 signaling pathway to promote GSH synthesis, thus, inhibiting oxidative stress. OI inhibited the early release of inflammatory and oxidative stress-related factors to reduce tissue and organ injury in mice with sepsis, while Nrf2 interfered with PD-L1 induction and inhibited PD-L1 expression at an advanced stage to reduce the occurrence of sepsis immunosuppression.

Conclusions: This study indicates that Nrf2 is a novel negative regulator of PD-L1 that functions at immune checkpoints and suggests an underlying mechanism for the anti-inflammatory process mediated by Nrf2.

Keywords: Itaconate, Sepsis, ROS, Nrf2, PD-L1, Macrophage


Citation styles

APA
Zhang, P., Wang, Y., Yang, W., Yin, Y., Li, C., Ma, X., Shi, L., Li, R., Tao, K. (2022). 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis. International Journal of Biological Sciences, 18(16), 6189-6209. https://doi.org/10.7150/ijbs.74456.

ACS
Zhang, P.; Wang, Y.; Yang, W.; Yin, Y.; Li, C.; Ma, X.; Shi, L.; Li, R.; Tao, K. 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis. Int. J. Biol. Sci. 2022, 18 (16), 6189-6209. DOI: 10.7150/ijbs.74456.

NLM
Zhang P, Wang Y, Yang W, Yin Y, Li C, Ma X, Shi L, Li R, Tao K. 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis. Int J Biol Sci 2022; 18(16):6189-6209. doi:10.7150/ijbs.74456. https://www.ijbs.com/v18p6189.htm

CSE
Zhang P, Wang Y, Yang W, Yin Y, Li C, Ma X, Shi L, Li R, Tao K. 2022. 4-Octyl itaconate regulates immune balance by activating Nrf2 and negatively regulating PD-L1 in a mouse model of sepsis. Int J Biol Sci. 18(16):6189-6209.

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