Peng Cheng, Tu Guangping, Wang Jiale, Wang Yilin, Wu Peng, Yu Li, Li Zhiqiang, Yu Xiao
Department of Hepatopancreatobiliary Surgery, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Radiology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Cell Death Dis. 2023 Feb 24;14(2):155. doi: 10.1038/s41419-023-05655-w.
Acute pancreatitis (AP) is a disease characterized by local and systemic inflammation with an increasing incidence worldwide. Receptor-interacting serine/threonine protein kinase 3 (RIPK3), mixed-lineage kinase domain-like protein (MLKL), and innate immune cell macrophages have been reported to be involved in the pathogenesis of AP. However, the mechanisms by which RIPK3 and MLKL regulate pancreatic injury, as well as the interactions between injured pancreatic acinar cells and infiltrating macrophages in AP, remain poorly defined. In the present study, experimental pancreatitis was induced in C57BL/6J, Ripk3 and Mlkl mice by cerulein plus lipopolysaccharide in vivo, and primary pancreatic acinar cells were also isolated to uncover cellular mechanisms during cerulein stimulation in vitro. The results showed that MLKL and its phosphorylated protein p-MLKL were upregulated in the pancreas of the mouse AP model and cerulein-treated pancreatic acinar cells, independent of its canonical upstream molecule Ripk3, and appeared to function in a cell death-independent manner. Knockout of Mlkl attenuated AP in mice by reducing the polarization of pancreatic macrophages toward the M1 phenotype, and this protective effect was partly achieved by reducing the secretion of CXCL10 from pancreatic acinar cells, whereas knockout of Ripk3 did not. In vitro neutralization of CXCL10 impaired the pro-M1 ability of the conditioned medium of cerulein-treated pancreatic acinar cells, whereas in vivo neutralization of CXCL10 reduced the polarization of pancreatic macrophages toward M1 and the severity of AP in mice. These findings suggested that targeting the MLKL-CXCL10-macrophage axis might be a promising strategy for the treatment of AP.
急性胰腺炎（AP）是一种以局部和全身炎症为特征的疾病，在全球范围内发病率呈上升趋势。据报道，受体相互作用丝氨酸/苏氨酸蛋白激酶3（RIPK3）、混合谱系激酶结构域样蛋白（MLKL）和固有免疫细胞巨噬细胞参与了AP的发病机制。然而，RIPK3和MLKL调节胰腺损伤的机制，以及AP中受损胰腺腺泡细胞与浸润巨噬细胞之间的相互作用，仍不清楚。在本研究中，通过在体内用雨蛙素加脂多糖诱导C57BL/6J、Ripk3和Mlkl小鼠发生实验性胰腺炎，并分离原代胰腺腺泡细胞以揭示体外雨蛙素刺激期间的细胞机制。结果表明，MLKL及其磷酸化蛋白p-MLKL在小鼠AP模型的胰腺和雨蛙素处理的胰腺腺泡细胞中上调，独立于其经典上游分子Ripk3，并且似乎以不依赖细胞死亡的方式发挥作用。敲除Mlkl可通过减少胰腺巨噬细胞向M1表型的极化来减轻小鼠的AP，这种保护作用部分是通过减少胰腺腺泡细胞中CXCL10的分泌来实现的，而敲除Ripk3则不能。体外中和CXCL10会损害雨蛙素处理的胰腺腺泡细胞条件培养基的促M1能力，而体内中和CXCL10则会降低胰腺巨噬细胞向M1的极化以及小鼠AP的严重程度。这些发现表明，靶向MLKL-CXCL10-巨噬细胞轴可能是治疗AP的一种有前景的策略。
