Hepatology communications · 2026
CD14+CD16- monocytes exhibit NF-κB hyperactivation in biliary atresia: Clinical association and murine therapeutic validation.
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Chang Jiaming, Liu Sizhe, Wu Xiaobin, Xu Qiying, Li Mengyue, Guo Zhipeng, Chen Hui, Wang Hezhen, Xu Lili, Yan Jingru, Fu Ming, Tao Boyuan, Chen Yan, Xia Huimin, Zhang Ruizhong, He Juan, Wen Zhe
Аннотация
BACKGROUND: Classical CD14+CD16- monocytes are elevated in biliary atresia (BA); however, their specific role in bile duct injury and the underlying regulatory mechanisms remain unclear. This study aimed to define their contribution to BA pathogenesis, focusing on the NF-κB signaling pathway.
METHODS: Liver tissues and blood samples from patients with BA and controls were analyzed by single-cell RNA sequencing, flow cytometry, and immunofluorescence. A rhesus rotavirus-induced BA mouse model was used for anti-Ly6C monocyte depletion and NF-κB inhibition (dehydroxymethylepoxyquinomicin). Transcriptomic profiling and cytokine analysis revealed key molecular mechanisms.
RESULTS: Classical monocytes were significantly enriched near the damaged bile ducts in patients with BA and positively correlated with liver injury severity. These monocytes exhibited NF-κB hyperactivation, marked by the upregulation of TNF, IL-1β, Cxcl2, and NLRP3 inflammasome components. RNA-seq revealed BA-specific monocyte clusters with enriched NF-κB signatures. The depletion of classical monocytes (anti-Ly6C) in rhesus rotavirus-induced BA mice reduced biliary inflammation, restored bile duct patency, and improved survival. Pharmacological NF-κB inhibition (dehydroxymethylepoxyquinomicin) similarly attenuated inflammation and liver dysfunction and improved survival in rhesus rotavirus-induced BA mice.
CONCLUSIONS: Classical CD14+CD16- monocytes are spatially enriched and exhibit NF-κB hyperactivation in BA. Targeting these cells or their NF-κB axis represents a promising therapeutic strategy to mitigate disease progression.
METHODS: Liver tissues and blood samples from patients with BA and controls were analyzed by single-cell RNA sequencing, flow cytometry, and immunofluorescence. A rhesus rotavirus-induced BA mouse model was used for anti-Ly6C monocyte depletion and NF-κB inhibition (dehydroxymethylepoxyquinomicin). Transcriptomic profiling and cytokine analysis revealed key molecular mechanisms.
RESULTS: Classical monocytes were significantly enriched near the damaged bile ducts in patients with BA and positively correlated with liver injury severity. These monocytes exhibited NF-κB hyperactivation, marked by the upregulation of TNF, IL-1β, Cxcl2, and NLRP3 inflammasome components. RNA-seq revealed BA-specific monocyte clusters with enriched NF-κB signatures. The depletion of classical monocytes (anti-Ly6C) in rhesus rotavirus-induced BA mice reduced biliary inflammation, restored bile duct patency, and improved survival. Pharmacological NF-κB inhibition (dehydroxymethylepoxyquinomicin) similarly attenuated inflammation and liver dysfunction and improved survival in rhesus rotavirus-induced BA mice.
CONCLUSIONS: Classical CD14+CD16- monocytes are spatially enriched and exhibit NF-κB hyperactivation in BA. Targeting these cells or their NF-κB axis represents a promising therapeutic strategy to mitigate disease progression.