Lipoprotein disorder is a common feature of chronic pancreatitis (CP); however, the relationship between lipoprotein disorder and pancreatic fibrotic environment is unclear. Here, we investigated the occurrence and mechanism of pancreatic stellate cell (PSC) activation by lipoprotein metabolites and the subsequent regulation of type 2 immune responses, as well as the driving force of fibrotic aggressiveness in CP. Single-cell RNA sequencing revealed the heterogeneity of PSCs and identified very-low-density lipoprotein receptor (VLDLR)⁺ PSCs that were characterized by a higher lipid metabolism. VLDLR promoted intracellular lipid accumulation, followed by interleukin-33 (IL-33) expression and release in PSCs. PSC-derived IL-33 strongly induced pancreatic group 2 innate lymphoid cells (ILC2s) to trigger a type 2 immune response accompanied by the activation of PSCs, eventually leading to fibrosis during pancreatitis. Our findings indicate that VLDLR-enhanced lipoprotein metabolism in PSCs promotes pancreatic fibrosis and highlight a dominant role of IL-33 in this pro-fibrotic cascade.

脂蛋白紊乱是慢性胰腺炎（CP）的一个共同特征；然而，脂蛋白紊乱与胰腺纤维化环境之间的关系尚不清楚。在这里，我们研究了脂蛋白代谢物激活胰腺星状细胞 (PSC) 的发生和机制，以及随后对 2 型免疫反应的调节，以及 CP 中纤维化侵袭性的驱动力。单细胞 RNA 测序揭示了 PSC 的异质性并鉴定了极低密度脂蛋白受体 (VLDLR) ⁺以较高的脂质代谢为特征的 PSC。VLDLR 促进细胞内脂质积累，随后是白细胞介素 33 (IL-33) 在 PSC 中的表达和释放。PSC 衍生的 IL-33 强烈诱导胰腺第 2 组先天淋巴细胞 (ILC2s) 引发伴随 PSC 活化的 2 型免疫反应，最终导致胰腺炎期间的纤维化。我们的研究结果表明，VLDLR 增强的 PSC 中的脂蛋白代谢促进了胰腺纤维化，并突出了 IL-33 在这种促纤维化级联反应中的主导作用。