Alkhani Anas, Baskaran Suruthi, Murti Abhishek, Rapp Blaine, Levy Claire S, Wang Bruce, Nijagal Amar
bioRxiv. 2024 Aug 19:2024.08.15.607661. doi: 10.1101/2024.08.15.607661.
Biliary atresia (BA) is a leading cause of liver failure in infants. Despite effective surgical drainage, patients with BA exhibit attenuated immune responses to childhood vaccines, suggesting there are long-lasting alterations to immune function. The perinatal liver is home to hematopoietic stem and progenitor cells (HSPCs) and serves as the epicenter for rapidly progressive and significantly morbid inflammatory diseases like BA. We have previously established the role of neonatal myeloid progenitors in the pathogenesis of perinatal liver inflammation (PLI) and hypothesize that PLI leads to long-term changes to HSPCs in mice that recovered from PLI. To test this hypothesis, we compared the changes that occur to HSPCs and mature myeloid populations in the bone marrow of adult mice during homeostasis and during PLI. Our results demonstrate that HSPCs from animals that recover from PLI ("PLI-recovered") undergo long-term expansion with a reduced proliferative capacity. Notably, PLI leads to persistent activation of common myeloid progenitors through the involvement of CXCL10 and its canonical receptor, CXCR3. Our data suggests that the CXCR3-CXCL10 axis may mediate the changes in HSPCs that lead to altered immune function observed in BA, providing support for a targetable pathway to mitigate the detrimental long-term immune effects observed in patients with BA.
胆道闭锁（BA）是婴儿肝衰竭的主要原因。尽管有有效的手术引流，但BA患者对儿童疫苗的免疫反应减弱，这表明免疫功能存在长期改变。围产期肝脏是造血干细胞和祖细胞（HSPCs）的所在地，也是像BA这种快速进展且具有显著病态的炎症性疾病的中心。我们之前已经确定了新生儿髓系祖细胞在围产期肝脏炎症（PLI）发病机制中的作用，并假设PLI会导致从小鼠PLI中恢复的HSPCs发生长期变化。为了验证这一假设，我们比较了成年小鼠在稳态和PLI期间骨髓中HSPCs和成熟髓系细胞群的变化。我们的结果表明，从PLI中恢复的动物（“PLI恢复”）的HSPCs会经历长期扩增，但其增殖能力降低。值得注意的是，PLI通过CXCL10及其经典受体CXCR3的参与导致常见髓系祖细胞持续激活。我们的数据表明，CXCR3-CXCL10轴可能介导了HSPCs的变化，这些变化导致了在BA中观察到的免疫功能改变，为减轻BA患者中观察到的有害长期免疫效应的可靶向途径提供了支持。
