RRC ID 58938
Author Koda Y, Nakamoto N, Chu PS, Ugamura 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.
Title Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35.
Journal J Clin Invest
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.
Volume 129(8)
Pages 3201-3213
Published 2019-7-2
DOI 10.1172/JCI125863
PII 125863
PMID 31264967
PMC PMC6668669
MeSH Adolescent Adult Aged Animals Dendritic Cells / immunology* Dendritic Cells / pathology Female Humans Interleukin-12 Subunit p35 / genetics Interleukin-12 Subunit p35 / immunology Interleukins / genetics Interleukins / immunology* Liver Failure, Acute / genetics Liver Failure, Acute / immunology* Liver Failure, Acute / pathology Liver Failure, Acute / prevention & control Male Membrane Glycoproteins / genetics Membrane Glycoproteins / immunology Mice Mice, Knockout Middle Aged Minor Histocompatibility Antigens / genetics Minor Histocompatibility Antigens / immunology Myeloid Differentiation Factor 88 / genetics Myeloid Differentiation Factor 88 / immunology Receptors, Cytokine / genetics Receptors, Cytokine / immunology T-Lymphocytes, Regulatory / immunology* T-Lymphocytes, Regulatory / pathology Toll-Like Receptor 7 / genetics Toll-Like Receptor 7 / immunology Toll-Like Receptor 9 / genetics Toll-Like Receptor 9 / immunology
IF 11.864
Times Cited 4
Mice RBRC05658