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

Yuzo Koda, Nobuhiro Nakamoto, Hakusyo Cho, Aya Yoshida, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalThe Journal of clinical investigation
Volume130
DOIs
Publication statusPublished - 2019 Jul 2

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Dendritic Cells
Liver
Wounds and Injuries
Acute Liver Failure
Immunosuppressive Agents
Concanavalin A
Liver Transplantation
Anti-Idiotypic Antibodies
Therapeutics

Keywords

  • Dendritic cells
  • Hepatitis
  • Hepatology
  • Immunotherapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. / Koda, Yuzo; Nakamoto, Nobuhiro; Cho, Hakusyo; Yoshida, Aya; Mikami, Yohei; Teratani, Toshiaki; Tsujikawa, Hanako; Shiba, Shunsuke; Taniki, Nobuhito; Sujino, Tomohisa; Miyamoto, Kentaro; Suzuki, Takahiro; Yamaguchi, Akihiro; Morikawa, Rei; Sato, Katsuaki; Sakamoto, Michiie; Yoshimoto, Takayuki; Kanai, Takanori.

In: The Journal of clinical investigation, Vol. 130, 02.07.2019.

Research output: Contribution to journalArticle

Koda, Y, Nakamoto, N, Cho, H, Yoshida, A, Mikami, Y, Teratani, T, Tsujikawa, H, Shiba, S, Taniki, N, Sujino, T, Miyamoto, K, Suzuki, T, Yamaguchi, A, Morikawa, R, Sato, K, Sakamoto, M, Yoshimoto, T & Kanai, T 2019, 'Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35', The Journal of clinical investigation, vol. 130. https://doi.org/10.1172/JCI125863
Koda, Yuzo ; Nakamoto, Nobuhiro ; Cho, Hakusyo ; Yoshida, Aya ; Mikami, Yohei ; Teratani, Toshiaki ; Tsujikawa, Hanako ; Shiba, Shunsuke ; Taniki, Nobuhito ; Sujino, Tomohisa ; Miyamoto, Kentaro ; Suzuki, Takahiro ; Yamaguchi, Akihiro ; Morikawa, Rei ; Sato, Katsuaki ; Sakamoto, Michiie ; Yoshimoto, Takayuki ; Kanai, Takanori. / Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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AU - Teratani, Toshiaki

AU - Tsujikawa, Hanako

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