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 1

Reduction of pDCs in the PB and liver of acute hepatitis patients.

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Reduction of pDCs in the PB and liver of acute hepatitis patients. PBMCs...
PBMCs were analyzed in healthy control (HC) (n = 21) subjects and in patients with acute viral hepatitis (VH) (n = 7), acute AIH (n = 8), and chronic AIH (n = 7). (A) Mean percentages of lineage–CD123+BDCA-2+ pDCs in PBMCs and (B) absolute numbers in the PB. Data are presented as box-and-whisker plots. IHC was performed on liver sections of patients suffering from hepatic metastasis with normal liver function (n = 6) as the controls and acute AIH patients (n = 5). **P < 0.01, ANOVA with Tukey’s multiple comparisons post-hoc test. (C) Representative photomicrographs of H&E-stained and BDCA-2 Ab–stained IHC sections of the liver. Arrowheads indicate BDCA-2–positive cells in patients with AIH. Scale bars: 100 μm. (D) Maximum cell numbers per unit area (1 mm2). Data are presented as box-and-whisker plots. **P < 0.01, Student t test. Black circles, males; white circles, females.