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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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 3

Siglec-H–dependent depletion of pDCs exacerbates ConA-induced inflammation.

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Siglec-H–dependent depletion of pDCs exacerbates ConA-induced inflammati...
(A) Representative Siglec-H and PDCA-1 staining of CD11b– cells (left), CD11b+CD11c+ cDCs (center), and CD11b+CD11c– monocytes/macrophages (right) in the liver CD45+ MNCs. (B) Study design. WT or Siglechdtr/+ mice were treated with DT 24 hours prior to ConA (15 mg/kg) or PBS injection. All mice were sacrificed and analyzed 18 hours after the ConA injection. (C) Representative B220 and PDCA-1 staining of CD45+CD11b––gated liver MNCs (left). Mean percentages of pDCs in CD45+ liver MNCs of the indicated mice (right). Data are shown as mean ± SEM (n = 4 for the control or control+pDC-depleted group; n = 7 for the ConA or ConA+pDCs-depleted group). **P < 0.01, Student’s t test. (D) Representative photomicrographs of H&E-stained sections of the liver. Scale bars: 500 μm. (E) Serum ALT levels. (F) Survival rate. (G) Cytokine concentrations in the serum of the indicated mice. (H) Mean percentages of various immune cells in CD45+-, CD45+TCRβ+-, or CD45+TCRβ+CD4+-gated liver MNCs of the indicated mice. Data are shown as mean ± SEM (n = 4 for the control or control +pDCs-depleted group; n = 7 for the ConA or ConA+pDCs-depleted group), except in the survival assay in which 20 mg/kg ConA was injected and the data are presented as a Kaplan-Meier curve (n = 18 per group). *P < 0.05; **P < 0.01, Student’s t test (C, E, G, and H) or log-rank test (F). Data are combined from 2 independent experiments.