CCR9 axis inhibition enhances hepatic migration of plasmacytoid DCs and protects against liver injury
Yuzo Koda, … , Michiie Sakamoto, Takanori Kanai
Yuzo Koda, … , Michiie Sakamoto, Takanori Kanai
Published August 9, 2022
Citation Information: JCI Insight. 2022;7(17):e159910. https://doi.org/10.1172/jci.insight.159910.
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Research Article Hepatology Immunology

CCR9 axis inhibition enhances hepatic migration of plasmacytoid DCs and protects against liver injury

Abstract

Plasmacytoid dendritic cells (pDCs) perform dual proinflammatory and immunosuppressive roles. We recently reported the potential of pDC therapy for treatment of intractable acute liver failure. However, establishment of efficient methods to deliver pDCs to the liver is essential for future clinical therapeutic applications. The present study demonstrates a higher abundance of liver and peripheral blood pDCs in mice lacking C-C motif chemokine receptor 9 (CCR9), a pDC gut-homing receptor, than in WT mice. Adoptive transfer of Ccr9–/– pDCs resulted in a higher efficiency of migration to the liver than WT pDCs did, while WT pDCs migrated efficiently to the original target organ, the small intestine. Further, Ccr9–/– pDCs consistently migrated efficiently to livers with concanavalin A–induced inflammation, and exerted a more effective immunosuppressive effect, resulting in better protection against acute liver inflammation than that demonstrated by WT pDCs. These findings highlight the therapeutic potential of the manipulation of the CCR9 axis as an approach to improve migration of immunosuppressive pDCs to the liver in order to exploit their beneficial effects in acute liver disease.

Authors

Yuzo Koda, Nobuhiro Nakamoto, Po-Sung Chu, Toshiaki Teratani, Akihisa Ueno, Takeru Amiya, Nobuhito Taniki, Sayako Chiba, Kentaro Miyamoto, Michiie Sakamoto, Takanori Kanai

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Figure 6

Adoptive transfer of Ccr9–/– pDCs improves protection against ConA-induced liver inflammation.

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Adoptive transfer of Ccr9–/– pDCs improves protection against ConA-induc...
(A) Study design. WT (Ly5.2) mice were injected i.v. with ConA (15 mg/kg) or PBS. An hour later, the mice were injected i.v. with FLT3L-proliferated BM pDCs from WT or Ccr9–/– mice (2 × 106 cells/200 μL PBS) or 200 μL PBS alone. All mice were sacrificed and analyzed 18 hours after ConA injection. (B) Mean percentages (left) and absolute numbers (right) of transferred BM pDCs (CD45.1) in the liver during ConA-induced hepatitis. (C) Representative photomicrographs of H&E-stained liver sections. Scale bars: 500 μm. (D–F) Serum ALT (D), AST (E), and IFN-γ (F) levels. (G) Study design. WT mice were injected i.v. with ConA (15 mg/kg) or PBS. Eight hours later, the mice were injected i.v. with FLT3L-proliferated BM pDCs from WT or Ccr9–/– mice (2 × 106 cells/200 μL PBS) or 200 μL PBS alone. All mice were sacrificed and analyzed 18 hours after ConA injection. (H and I) Serum ALT (H) and AST (I) levels. Data represent the mean ± SEM (n = 6 per group). *P < 0.05, **P < 0.01, Student’s t test (B) or ANOVA with Tukey’s multiple-comparison post hoc test (D–F, H, and I). Data are combinations of 2 independent experiments (B, D–F, H, and I).