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 August 1, 2019; First published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3201-3213. https://doi.org/10.1172/JCI125863.
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Research Article Hepatology

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 5

Suppressive effect of BM-derived pDCs on ConA-induced inflammation is dependent on IL-35.

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Suppressive effect of BM-derived pDCs on ConA-induced inflammation is de...
(A) Relative changes of the serum cytokine concentration in pDC-ConA–treated mice compared with ConA-treated mice. Data are shown as mean fold changes + SEM (n = 7) (left). Concentrations of IL-10, IL-27, and IL-35 in the serum of the indicated mice. Data are shown as mean ± SEM (n = 7 for the ConA or ConA+pDC group) (right). **P < 0.01, Student’s t test. (B) Study design. WT mice were treated with anti–IL-35 monoclonal Ab or isotype control (200 μg/head) intraperitoneally 6 hours prior to ConA (15 mg/kg) or PBS injection. One hour later, mice were inoculated intravenously 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 the ConA injection. (C) Serum ALT levels. Data are shown as mean ± SEM (n = 8 per group). **P < 0.01, ANOVA with Tukey’s multiple comparisons post-hoc test. (D) Representative intracellular IFN-γ and IL-17A staining of CD45+TCRβ+CD4+-gated liver MNCs. (E) Mean percentages of IFN-γ+ (Th1) cells (left) and IL-17+ (Th17) cells (right) in CD45+TCRβ+CD4+-gated liver MNCs. (F) Irf1 gene expression levels in whole livers from the indicated mice. Data are shown as mean ± SEM (n = 7 per group). *P < 0.05; **P < 0.01, ANOVA with Tukey’s multiple comparisons post-hoc test. Data are combined from 2 independent experiments.