Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Front Immunol. 2020 Mar 18;11:307. doi: 10.3389/fimmu.2020.00307. eCollection 2020.
SHIP-1 is an inositol phosphatase that hydrolyzes phosphatidylinositol 3-kinase (PI3K) products and negatively regulates protein kinase B (Akt) activity, thereby modulating a variety of cellular processes in mammals. However, the role of SHIP-1 in bacterial-induced sepsis is largely unknown. Here, we show that SHIP-1 regulates inflammatory responses during Gram-negative bacterium infection. We found that infected-SHIP-1 mice exhibited decreased survival rates, increased inflammatory responses, and susceptibility owing to elevated expression of PI3K than wild-type (WT) mice. Inhibiting SHIP-1 siRNA silencing resulted in lipid raft aggregates, aggravated oxidative damage, and bacterial burden in macrophages after PAO1 infection. Mechanistically, SHIP-1 deficiency augmented phosphorylation of PI3K and nuclear transcription of signal transducer and activator of transcription 5 (STAT5) to induce the expression of Trib1, which is critical for differentiation of M2 but not M1 macrophages. These findings reveal a previously unrecognized role of SHIP-1 in inflammatory responses and macrophage homeostasis during infection through a PI3K/Akt-STAT5-Trib1 axis.
SHIP-1 是一种肌醇磷酸酶，可水解磷酸肌醇 3-激酶（PI3K）产物，负调控蛋白激酶 B（Akt）活性，从而调节哺乳动物中的各种细胞过程。然而，SHIP-1 在细菌诱导的败血症中的作用在很大程度上尚不清楚。在这里，我们表明 SHIP-1 调节革兰氏阴性菌感染期间的炎症反应。我们发现，与野生型（WT）小鼠相比，感染 SHIP-1 的小鼠表现出存活率降低、炎症反应增强和易感性增加，这是由于 PI3K 的表达升高所致。抑制 SHIP-1 的 siRNA 沉默导致脂质筏聚集，在 PAO1 感染后加剧巨噬细胞中的氧化损伤和细菌负荷。在机制上，SHIP-1 缺乏会增强 PI3K 的磷酸化和信号转导和转录激活因子 5（STAT5）的核转录，从而诱导 Trib1 的表达，这对于 M2 但不是 M1 巨噬细胞的分化至关重要。这些发现揭示了 SHIP-1 通过 PI3K/Akt-STAT5-Trib1 轴在感染期间在炎症反应和巨噬细胞动态平衡中发挥的以前未被认识的作用。
