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Nrf2 activation mediates tumor-specific hepatic stellate cells-induced DIgR2 expression in dendritic cells
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 mechani...
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Published in: | Aging (Albany, NY.) NY.), 2019-12, Vol.11 (23), p.11565-11575 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 1945-4589 |
DOI: | 10.18632/aging.102554 |