Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, 610041, China.
Lab of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 1, 4th Keyuan Road, Chengdu, 610041, China.
Cell Mol Life Sci. 2023 Nov 27;80(12):379. doi: 10.1007/s00018-023-05032-y.
B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-β signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-β or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.
B 细胞可以促进肝纤维化，但 B 细胞浸润的机制和针对致病 B 细胞的治疗方法仍有待研究。我们假设通过阻断 CXCL12-CXCR4 轴，可以破坏胆管细胞与 B 细胞的相互作用，从而减轻肝纤维化，这一作用是通过塞来昔布的 COX-2 非依赖性来实现的。在硫代乙酰胺处理的野生型小鼠中，塞来昔布改善了淋巴细胞浸润和肝纤维化。通过单细胞 RNA 测序和流式细胞术，确定 CXCR4 是致纤维化和肝归巢表型 B 细胞的标志物。塞来昔布减少了肝归巢 B 细胞，但不抑制 CXCR4。胆管细胞表达 CXCL12，吸引 B 细胞向人和小鼠的纤维化区域迁移。塞来昔布抑制了胆管细胞的增殖和 CXCL12 的表达。在 CXCL12 缺陷型小鼠中，肝纤维化也减轻，B 细胞浸润减少。在肝内胆管上皮细胞系 HIBEpiC 中，批量 RNA 测序表明，塞来昔布和 2,5-二甲基塞来昔布（一种不表现出 COX-2 依赖性的塞来昔布类似物）均调节 TGF-β 信号通路和细胞周期。此外，塞来昔布和 2,5-二甲基塞来昔布降低了 TGF-β或 EGF 刺激的 HIBEpiC 细胞的增殖和胶原 I 和 CXCL12 的表达。综上所述，通过阻断 CXCL12-CXCR4 轴，塞来昔布的 COX-2 非依赖性作用可以破坏胆管细胞与 B 细胞的相互作用，从而减轻肝纤维化。
