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Aging (Albany NY). 2019 Dec 13;11. doi: 10.18632/aging.102554. [Epub ahead of print]

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

Author information

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.

Abstract

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.

KEYWORDS:

DIgR2; Nrf2 signaling; dendritic cells; hepatic stellate cells (tHSCs); hepatocellular carcinoma (HCC)

PMID:
31831714
DOI:
10.18632/aging.102554
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