Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/β release.

中文翻译：

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Ptpn6 抑制 caspase-8 和 Ripk3/Mlkl 依赖性炎症。

Ptpn6 是一种细胞质磷酸酶，可预防自身免疫性和白介素-1 (IL-1) 受体依赖性、caspase-1 非依赖性炎症性疾病。中性粒细胞中 Ptpn6 的条件性缺失 (Ptpn6ΔPMN) 足以引发 IL-1 受体依赖性皮肤炎症性疾病，但 IL-1 的来源和 IL-1 释放背后的机制仍不清楚。在这里，我们研究了通过抑制 caspase-8 依赖性细胞凋亡和 Ripk1-Ripk3-Mlkl 调节的坏死性凋亡来控制中性粒细胞释放 IL-1α/β 的机制。Ripk1 的缺失加速了疾病的发作，而 caspase-8 和 Ripk3 或 Mlkl 的联合缺失强烈保护了 Ptpn6ΔPMN 小鼠。Ptpn6ΔPMN 中性粒细胞显示 p38 丝裂原活化蛋白激酶依赖性 Ripk1 非依赖性 IL-1 和肿瘤坏死因子产生增加，并且容易发生细胞死亡。总之，这些数据强调了 Ptpn6 的双重功能，即负调节 p38 丝裂原活化蛋白激酶激活以控制肿瘤坏死因子和 IL-1α/β 表达，以及维持 Ripk1 功能以防止 caspase-8- 和 Ripk3-Mlkl-依赖性细胞死亡和伴随的 IL-1α/β 释放。