Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35
Yuzo Koda, … , Takayuki Yoshimoto, Takanori Kanai
Yuzo Koda, … , Takayuki Yoshimoto, Takanori Kanai
Published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3201-3213. https://doi.org/10.1172/JCI125863.
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Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

Abstract

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A–induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35–dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35–deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.

Authors

Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Aya Ugamura, Yohei Mikami, Toshiaki Teratani, Hanako Tsujikawa, Shunsuke Shiba, Nobuhito Taniki, Tomohisa Sujino, Kentaro Miyamoto, Takahiro Suzuki, Akihiro Yamaguchi, Rei Morikawa, Katsuaki Sato, Michiie Sakamoto, Takayuki Yoshimoto, Takanori Kanai

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Figure 6

BM-derived pDCs ameliorate ConA-induced inflammation in the presence of IL-35–producing Tregs.

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BM-derived pDCs ameliorate ConA-induced inflammation in the presence of ...
(A) IL-35–related gene expression levels in liver CD45+TCRβ+CD4+CD25+CD45RBlo Tregs isolated from the indicated mice. Data are shown as mean ± SEM (n = 6 per group). **P < 0.01, ANOVA with Tukey’s multiple comparisons post-hoc test. (B) Study design. WT mice were treated with anti-CD25 Ab (PC61) or isotype control (500 μg/head) intraperitoneally 6 hours prior to ConA (15 mg/kg) or PBS injection. One hour later, mice were intravenously inoculated with Flt-3L–proliferated BM-derived pDCs (2 × 106 cells/200 μL PBS) or 200 μL PBS alone. All mice were sacrificed and analyzed 18 hours after ConA injection. (C) Mean percentages of CD25+cells in CD45+TCRβ+CD4+-gated liver MNCs. (D) Representative Foxp3 and CD4 intracellular staining of CD45+TCRβ+CD4+-gated liver MNCs (left) and mean percentages of Foxp3+ Tregs in CD45+TCRβ+CD4+-gated liver MNCs (right) of indicated mice. Data are shown as mean ± SEM (n = 3 per group). **P < 0.01, ANOVA with Tukey’s multiple comparisons correction. (E) Serum IL-35 concentrations of indicated mice. (F) Serum ALT levels of the indicated mice. Data are shown as mean ± SEM (n = 7 for the control IgG or control IgG+pDC group; n = 8 for the anti-CD25 Ab or anti-CD25 Ab+pDC group). **P < 0.01, ANOVA with Tukey’s multiple comparisons post-hoc test. Data are representative (C and D) or combined (A, E, and F) from 2 independent experiments.