Tissue-plasminogen activator (tPA) is a serine protease well known for its fibrinolytic function. Recent studies indicate that tPA could also modulate inflammation via plasmin generation and/or by receptor mediated signalling in vitro. However, the contribution of tPA in inflammatory processes in vivo has not been fully addressed. Therefore, using tPA-deficient mice, we have analysed the effect of lipopolysaccharide (LPS) challenge on the phenotype of myeloid cells including neutrophils, macrophages and dendritic cells (DCs) in spleen. We found that LPS treatment upregulated the frequency of major histocompatibility class two (MHCII+) macrophages but also, paradoxically, induced a deep downregulation of MHCII molecule level on macrophages and on conventional dendritic cells 2 (cDC2). Expression level of the CD11b integrin, known as a tPA receptor, was upregulated by LPS on MHCII+ macrophages and cDC2, suggesting that tPA effects could be amplified during inflammation. In tPA−/− mice under inflammatory conditions, expression of costimulatory CD86 molecules on MHCII+ macrophages was decreased compared to WT mice, while in steady state the expression of MHCII molecules was higher on macrophages. Finally, we reported that tPA deficiency slightly modified the phenotype of DCs and T cells in acute inflammatory conditions. Overall, our findings indicate that in vivo, LPS injection had an unexpectedly bimodal effect on MHCII expression on macrophages and DCs that consequently might affect adaptive immunity. tPA could also participate in the regulation of the T cell response by modulating the levels of CD86 and MHCII molecules on macrophages.

中文翻译：

---

组织纤溶酶原激活剂对急性炎症中脾髓细胞表型的影响

组织纤溶酶原激活剂 (tPA) 是一种丝氨酸蛋白酶，以其纤溶功能而闻名。最近的研究表明，tPA 还可以通过纤溶酶生成和/或体外受体介导的信号传导来调节炎症。然而，tPA 在体内炎症过程中的作用尚未得到充分解决。因此，使用tPA缺陷小鼠，我们分析了脂多糖（LPS）攻击对脾脏中包括中性粒细胞、巨噬细胞和树突状细胞（DC）在内的骨髓细胞表型的影响。我们发现 LPS 处理上调了主要组织相容性 2 类 (MHCII+) 巨噬细胞的频率，但矛盾的是，还诱导了巨噬细胞和传统树突状细胞 2 (cDC2) 上 MHCII 分子水平的深度下调。 MHCII+巨噬细胞和cDC2上的CD11b整合素（称为tPA受体）的表达水平被LPS上调，这表明tPA效应在炎症过程中可能会被放大。在炎症条件下的 tPA−/− 小鼠中，与 WT 小鼠相比，MHCII+ 巨噬细胞上共刺激 CD86 分子的表达降低，而在稳定状态下，巨噬细胞上 MHCII 分子的表达较高。最后，我们报道了 tPA 缺乏略微改变了急性炎症条件下 DC 和 T 细胞的表型。总体而言，我们的研究结果表明，在体内，LPS 注射对巨噬细胞和 DC 上的 MHCII 表达具有意想不到的双峰效应，因此可能会影响适应性免疫。 tPA 还可以通过调节巨噬细胞上 CD86 和 MHCII 分子的水平来参与 T 细胞反应的调节。