Periportal macrophages protect against commensal-driven liver inflammation [spatial transcriptomics]

The liver is the main gateway from the gut and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zonation, such as peri-portal vein (PV) and peri-central vein (CV) zones; however, the functional and molecular differences among liver macrophages in these zones remain poorly understood. Here, intravital multiphoton imaging revealed significantly suppressed in PV zones. Zonation-specific single-cell transcriptome analyses detected an immuno-suppressive macrophage subset highly expressing IL-10 and Marco, a scavenger receptor, enriched in PV zones. Inhibited IL-10 signaling and Marco-deficient conditions impaired the suppressive function of these macrophages. The reduced number of Marco-positive suppressive macrophages in germ-free or antibiotic-treated conditions suggested that gut commensal bacteria were responsible for inducing this specific population. Dextran sulfate sodium-induced colitis led to inflammation in liver PV zones, which was more prominent under Marco-deficient conditions. Marco-positive inflammatory macrophages in the human liver are diminished in primary sclerosing cholangitis (PSC), an intractable disease characterized by chronic inflammation around the portal veins and bile ducts. Collectively, commensal bacteria and their pathogenic substances induce Marco-positive immunosuppressive macrophages, consequently limiting excessive inflammation in PV zones. Failure of this self-limiting system may cause hepatic inflammatory disorders, such as PSC. Spatial transcriptome analysis on the healthy mouse liver using 10X Visium肝脏是肠道的核心门户，从门静脉至中央静脉的单向窦状血流造就了肝脏的异质性分区，例如门静脉周围区（peri-portal vein, PV）与中央静脉周围区（peri-central vein, CV）；然而目前学界对这些分区内肝脏巨噬细胞的功能与分子差异仍缺乏深入认知。本研究通过活体多光子成像发现，门静脉周围区域的相关免疫活性显著受抑。分区特异性单细胞转录组分析检测到一类高表达IL-10与清道夫受体Marco的免疫抑制性巨噬细胞亚群，该亚群在门静脉周围区域中富集。阻断IL-10信号通路以及Marco基因缺陷均可损害这类巨噬细胞的免疫抑制功能。无菌小鼠或经抗生素处理的小鼠体内，Marco阳性免疫抑制性巨噬细胞的数量显著减少，这提示肠道共生菌参与诱导了这一特异性巨噬细胞亚群的产生。右旋葡聚糖硫酸钠（dextran sulfate sodium, DSS）诱导的结肠炎可引发肝脏门静脉周围区域的炎症反应，且该炎症表型在Marco基因缺陷小鼠中更为突出。原发性硬化性胆管炎（primary sclerosing cholangitis, PSC）是一类以门静脉及胆管周围慢性炎症为特征的难治性疾病，患者肝脏内的Marco阳性炎性巨噬细胞数量明显减少。综上，肠道共生菌及其致病相关物质可诱导产生Marco阳性免疫抑制性巨噬细胞，从而限制门静脉周围区域的过度炎症反应。这一自我限炎系统的功能异常可能引发诸如原发性硬化性胆管炎在内的肝脏炎症性疾病。本研究同时使用10X Visium平台对健康小鼠肝脏开展了空间转录组分析。