四塩化炭素の腹腔内投与によるマウス肝線維化促進の機序として, ①CCL25/CCR9を介したマクロファージ, および星細胞の炎症の場への遊走, さらに②CCR9陽性マクロファージによるTNF-αおよびTGF-β依存的な星細胞の活性化が重要であると考えられた。さらにConcanavalin Aの静脈内投与によるマウス急性肝障害モデルにおいて, 肝臓への炎症性マクロファージや抑制性樹状細胞の集積に加えて, Bacteroides属, およびLactobacillus属をはじめとする腸内細菌叢の経時的な変化が認められ, 肝臓内免疫細胞との相互作用により免疫応答, 免疫寛容が巧妙に制御されている可能性が示された。
We report that TNFα-producing CCR9+ macrophages infiltrated during the process of CCl4-induced liver fibrosis, and CCR9 deficiency protects the liver from overt fibrosis. Liver-infiltrating CD11b+ macrophages from CCl4-treated WT mice (CCR9+ macrophages), but not CD8+ T lymphocytes or non-CD11b+ cells, showed a significantly superior ability to activate HSCs over those from CCR9-/- mice in vitro.
Following Concanavalin A administration, a murine model of acute liver injury, in addition to the accumulation of inflammatory macrophages and suppressive dendritic cells in the liver, the composition of intestinal bacterial flora such as Genus Bacteroides and Genus Lactobacillus sequentially changed. Transplantation of fecal microbiota derived from mice post-ConA administration, but not from untreated mice, to gut sterilized mice induced immunosuppressive CD11c+ cDCs in the liver and reduced liver injury by ConA.
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