Research Paper Volume 11, Issue 23 pp 11565—11575

Nrf2 activation mediates tumor-specific hepatic stellate cells-induced DIgR2 expression in dendritic cells

Yun-Hong Xia 1, *, , Zhen Lu 2, *, , Shou-Min Wang 1, , Li-Xia Hu 3, ,

  • 1 Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China
  • 2 Department of General Surgery, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, China
  • 3 Department of Oncology, Hefei Hospital, Anhui Medical University, Hefei, China
* Co-first authors

received: September 21, 2019 ; accepted: November 20, 2019 ; published: December 13, 2019 ;
How to Cite

Copyright © 2019 Xia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Our previous studies discovered that tumor-specific hepatic stellate cells (tHSCs) induced dendritic cell-derived immunoglobulin receptor 2 (DIgR2) expression in bone marrow-derived dendritic cells (mDCs), inhibiting splenic T cell activation. The current study aims to explore the underlying mechanism of DIgR2 expression by focusing on Nrf2 (nuclear-factor-E2-related factor 2) signaling. We show that tHSCs co-culture induced significant Nrf2 signaling activation in mDCs. The latter was evidenced by Nrf2-Keap1 disassociation, Nrf2 protein stabilization, accumulation and nuclear translocation. Expression of Nrf2-dependent genes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), were detected in tHSCs-co-cultured mDCs. Importantly tHSCs-induced DIgR2 expression was blocked by Nrf2 shRNA or knockout (KO, by CRISPR/Cas9 method). Conversely, forced activation of Nrf2, by Keap1 shRNA or the Nrf2 activators (3H-1,2-dithiole-3-thione and MIND4-17), induced significant DIgR2 expression. tHSCs stimulation induced reactive oxygen species (ROS) production in mDCs. Conversely, ROS scavengers inhibited tHSCs-induced ROS production, Nrf2 activation and DIgR2 expression in mDCs. Significantly, tHSCs inhibited production of multiple cytokines (CD80, CD86 and IL-12) in mDCs, reversed by Nrf2 depletion. Moreover, Nrf2 shRNA or KO attenuated splenic T cell inhibition by tHSCs-stimulated mDCs. Together, we conclude that Nrf2 activation mediates tHSCs-induced DIgR2 expression in mDCs.


ARE: Anti-oxidant response element; APC: antigen-presenting cells; mDCs: bone marrow-derived dendritic cells; Co-IP: co-immunoprecipitation; CTL: cytotoxic T lymphocyte; DCs: dendritic cells; DigR2: dendritic cell-derived immunoglobulin receptor 2; HCC: hepatocellular carcinoma; HSC: hepatic stellate cells; HO-1: heme oxygenase-1; ICAM-1: intercellular adhesion molecule 1; IFN-γ: interferon-γ; Keap1: Kelch-like ECH-associated protein 1; LPS: lipopolysaccharides; NAC: N-acetylcysteine; NQO1: NAD(P)H:quinone oxidoreductase 1; Nrf2: nuclear-factor-E2-related factor 2; OVA-II: ovalbumin II; qPCR: quantitative real-time PCR; ROS: reactive oxygen species; SD: standard deviation; JC-1: Tetraethylbenzimidazolylcarbocyanine iodide; tHSCs: tumor-specific hepatic stellate cells; VCAM-1: vascular cell adhesion molecule 1.