INSERM U1138, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, F-75006 Paris, France.
Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Biochem J. 2020 Oct 30;477(20):4037-4051. doi: 10.1042/BCJ20200699.
Renal epithelial cells regulate the destructive activity of macrophages and participate in the progression of kidney diseases. Critically, the Unfolded Protein Response (UPR), which is activated in renal epithelial cells in the course of kidney injury, is required for the optimal differentiation and activation of macrophages. Given that macrophages are key regulators of renal inflammation and fibrosis, we suppose that the identification of mediators that are released by renal epithelial cells under Endoplasmic Reticulum (ER) stress and transmitted to macrophages is a critical issue to address. Signals leading to a paracrine transmission of ER stress (TERS) from a donor cell to a recipient cells could be of paramount importance to understand how ER-stressed cells shape the immune microenvironment. Critically, the vast majority of studies that have examined TERS used thaspigargin as an inducer of ER stress in donor cells in cellular models. By using multiple sources of ER stress, we evaluated if human renal epithelial cells undergoing ER stress can transmit the UPR to human monocyte-derived macrophages and if such TERS can modulate the inflammatory profiles of these cells. Our results indicate that carry-over of thapsigargin is a confounding factor in chemically based TERS protocols classically used to induce ER Stress in donor cells. Hence, such protocols are not suitable to study the TERS phenomenon and to identify its mediators. In addition, the absence of TERS transmission in more physiological models of ER stress indicates that cell-to-cell UPR transmission is not a universal feature in cultured cells.
肾上皮细胞调节巨噬细胞的破坏活性，并参与肾脏疾病的进展。至关重要的是，在肾脏损伤过程中肾上皮细胞中激活的未折叠蛋白反应 (UPR) 是巨噬细胞最佳分化和激活所必需的。鉴于巨噬细胞是肾脏炎症和纤维化的关键调节因子，我们假设鉴定在内质网 (ER) 应激下由肾上皮细胞释放并传递给巨噬细胞的介质是解决的关键问题。导致从供体细胞到受体细胞的 ER 应激旁分泌传递 (TERS) 的信号对于理解 ER 应激细胞如何塑造免疫微环境可能至关重要。至关重要的是，绝大多数研究使用 thapsigargin 作为细胞模型中供体细胞 ER 应激的诱导剂来检查 TERS。通过使用多种 ER 应激源，我们评估了经历 ER 应激的人肾上皮细胞是否可以将 UPR 传递给人单核细胞衍生的巨噬细胞，以及这种 TERS 是否可以调节这些细胞的炎症特征。我们的结果表明，在经典地用于诱导供体细胞 ER 应激的基于化学的 TERS 方案中， thapsigargin 的转移是一个混杂因素。因此，此类方案不适合研究 TERS 现象及其介质。此外，在更生理的 ER 应激模型中缺乏 TERS 传递表明细胞间 UPR 传递不是培养细胞的普遍特征。
