The Walter and Eliza Hall Institute, Parkville, VIC, Australia.
The University of Melbourne, Department of Medical Biology, Parkville, VIC, Australia.
Cell Death Differ. 2023 Apr;30(4):1059-1071. doi: 10.1038/s41418-023-01121-4. Epub 2023 Feb 8.
MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl and Ripk3 mice on a congenic C57BL/6 J genetic background. We show that genetic deletion of Mlkl in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. -Seventeen-month-old Mlkl female mice were also protected against age-related chronic sterile inflammation in connective tissue and skeletal muscle relative to wild-type littermate controls, exhibiting a reduced number of immune cell infiltrates in these sites and fewer regenerating myocytes. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans.
MLKL 和 RIPK3 是炎症细胞死亡途径（细胞坏死）的核心信号蛋白，细胞坏死是人类疾病的已知介质和调节剂。细胞坏死几乎涉及每个生理系统疾病的进展，最近的报告表明细胞坏死在衰老中起作用。在这里，我们在一个具有同源 C57BL/6J 遗传背景的 Mlkl 和 Ripk3 小鼠队列中，首次对与年龄相关的组织病理学和免疫学表型进行了全面分析。我们发现，在雌性小鼠中基因敲除 Mlkl 会中断免疫系统衰老，特别是延迟与年龄相关的循环淋巴细胞减少。与野生型同窝对照相比，17 个月大的 Mlkl 雌性小鼠还能抵抗结缔组织和骨骼肌的与年龄相关的慢性无菌性炎症，这些部位的免疫细胞浸润减少，再生肌细胞减少。这些观察结果表明 MLKL 与与年龄相关的无菌性炎症有关，这表明长期抗细胞坏死疗法在人类中可能有应用。
