常山幸一先生らの論文「Autophagy of Kupffer cells modulates CD8+ T cell activation in primary biliary cholangitis.」が掲載されました。

 

掲載誌等：Gut, 75, 9, 1831-1844, 2026.
DOI：10.1136/gutjnl-2025-335611
著者：Pan-Yue Luo, Min Ma, Meng-Chu Liu, Ye-Hui Wu, Jie Long, Meng-Xing Huang, Si-Yu Yang, Tian-Tian Da, Koichi Tsuneyama, Qiao Li, Haosheng Jin, Zhi-Bin Zhao, Jun Wang, Xiong Ma, Eric Merrill Gershwin, Ying Han, Zhe-Xiong Lian and Liang Li

 

要約：Kupffer cells and monocyte-derived macrophages (MoMs) are difficult to study in human primary biliary cholangitis (PBC) even though they reflect a dynamic hepatic immune population. We aim to investigate the role of hepatic macrophage and its therapeutic potential in human PBC and murine autoimmune cholangitis. Phenotypic analysis of hepatic macrophages in patients with PBC and dnTGFβRII mice model was performed by single-cell RNA sequencing, flow cytometry and immunohistochemistry. Depletion of hepatic macrophages and inhibition of MoMs were performed in murine autoimmune cholangitis. Lyz2-Cre-mediated Atg5 knockout mice and co-culture experiments were applied to explore the role and mechanism of macrophage autophagy in autoimmune cholangitis. Therapeutic intervention was performed using nanoparticle-capsuled small interfering RNA against Atg5. Kupffer cells from patients with PBC and dnTGFβRII mice upregulate genes associated with inflammatory responses and exhibit increased autophagy. Further, macrophage-specific knockout of Atg5 leads to reduction of inflammation and bile duct damage. We propose that the mechanism of this modulation is secondary to decreased activation of pathogenic CD8+ T cells. Indeed, Kupffer cells maintain CD8+ T cell tolerance through expression of inducible nitric oxide synthase (iNOS) and generation of NO. Increased autophagy resulted in degradation of iNOS in Kupffer cells and abrogated their suppressive activity against CD8+ T cells. Finally, we report that targeted downregulation of Kupffer cell autophagy in vivo using cationic lipid-assisted nanoparticles encapsulating siRNA against Atg5 leads to reduction of liver inflammation and bile duct damage. Macrophage autophagy promotes autoimmune cholangitis and strongly supports this pathway as a potential therapeutic target.