Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35
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
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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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 2

Reduction of pDCs in the PB and liver during ConA-induced inflammation in mice.

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Reduction of pDCs in the PB and liver during ConA-induced inflammation i...
(A) Representative B220 and PDCA-1 staining of CD45+CD11b–-gated BM, spleen, liver, and small intestinal epithelium (S-IE) MNCs in male C57BL/6 mice (left). Representative Siglec-H (center) and CCR9 (right) histograms of CD45+CD11b–B220+PDCA-1+ pDCs in the BM, spleen, liver, and small intestinal epithelium. (B) Mean percentages of pDCs in CD45+ BM, PB, spleen, liver, small-intestine lamina propria (S-LP), small intestinal epithelium, colon lamina propria (C-LP), colon intestinal epithelium (C-IE), Peyer’s patches (PP), mesenteric lymph nodes (MLN), axillary lymph nodes (ALN), and thymus MNCs. Data are shown as mean ± SEM (n = 4 per organ). (C) Mean percentages (upper panels) and absolute numbers (lower panels) of pDCs in CD45+ liver (left), PB (center), and BM (right) MNCs of mice analyzed 18 hours following PBS (control) or ConA injection. Data are shown as mean ± SEM (n = 4 per group). **P < 0.01, Student’s t test. Data are representative of over 3 independent experiments.