Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Graduate Institute of Clinical Medicine Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Microbiol Immunol Infect. 2018 Apr;51(2):166-173. doi: 10.1016/j.jmii.2016.07.002. Epub 2016 Aug 3.
BACKGROUND/PURPOSE: Viral infections and innate immunity signaling, especially Toll-like receptor 7 (TLR7) have been implicated in the pathogenesis of biliary atresia (BA). Administration of rhesus rotavirus-type A to newborn Balb/c mice produces inflammatory obstruction of bile ducts, which resembles human BA. However, whether activation of TLR7 signaling plays a role in neonatal hepatobiliary injury remains to be investigated.
TLR7 agonist, imiquimod (R837), was intraperitoneally administered to Balb/c mice within 24 hours of birth and then every other day. Morphological and histological injuries of liver and gallbladder were examined at 2 weeks. Hepatic messenger RNA expression of TLR7 signaling was studied. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling staining was used to delineate hepatobiliary apoptosis upon TLR7 stimulation.
TLR7 agonist, imiquimod, induced hypoplasia of the biliary system of neonatal Balb/c mice both in atrophic gallbladder and in paucity of intrahepatic bile ducts. There was significantly higher hepatic expression of TLR7 and downstream innate immunity-mediated interferon regulatory factor 7, interferon-α, and tumor necrosis factor-α. In addition, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling-positive cells in the liver were increased after injections of TLR7 agonist.
The results demonstrate that TLR7 activation may trigger innate immunity pathways and induce apoptosis and hypoplasia of neonatal biliary trees in Balb/c mice. The novel findings give an implication of pathogenesis of infantile cholestasis, such as BA.
背景/目的：病毒感染和先天免疫信号，特别是 Toll 样受体 7（TLR7），已被认为与胆道闭锁（BA）的发病机制有关。给新生 Balb/c 小鼠注射恒河猴轮状病毒 A 会导致胆管炎症性阻塞，类似于人类 BA。然而，TLR7 信号的激活是否在新生儿肝胆损伤中起作用仍有待研究。
TLR7 激动剂咪喹莫特（R837）在新生 Balb/c 小鼠出生后 24 小时内腹腔内给药，然后每隔一天给药一次。在 2 周时检查肝和胆囊的形态和组织学损伤。研究 TLR7 信号转导的肝信使 RNA 表达。末端脱氧核苷酸转移酶 2'-脱氧尿苷 5'-三磷酸末端标记染色用于描绘 TLR7 刺激后的肝胆细胞凋亡。
TLR7 激动剂咪喹莫特诱导新生 Balb/c 小鼠胆道系统发育不良，表现为萎缩性胆囊和肝内胆管稀少。TLR7 和下游先天免疫介导的干扰素调节因子 7、干扰素-α和肿瘤坏死因子-α的肝表达显著增加。此外，TLR7 激动剂注射后肝脏中的末端脱氧核苷酸转移酶 2'-脱氧尿苷 5'-三磷酸末端标记阳性细胞增加。
结果表明，TLR7 激活可能触发先天免疫途径，并诱导 Balb/c 小鼠新生胆道树的凋亡和发育不良。新发现提示了婴儿期胆汁淤积症（如 BA）的发病机制。
