Center for Immunity, Inflammation, and Regenerative Medicine, Departments of Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Center for Immunity, Inflammation, and Regenerative Medicine, Departments of Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA; Division of Rheumatology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
J Autoimmun. 2020 Jan;106:102331. doi: 10.1016/j.jaut.2019.102331. Epub 2019 Sep 5.
Inflammation plays a key role in the pathogenesis of lupus nephritis (LN) and inflammatory cytokines within the glomeruli are critical in this process. However, little information is available for the identities of the cell types that are primarily responsible for the production and function of the various cytokines. We have devised a novel method to visualize cytokine signals in the kidney by confocal microscopy and found that cytokine production within the glomerulus is cell type-specific and under translational control. In the lupus-prone NZM2328 mice with chronic glomerulonephritis, IL-6, IL-1β, and TNF-α in the glomerulus were produced predominantly by mesangial cells, podocytes, and glomerulus-infiltrating blood-derived macrophages, respectively. Microarray and RNASeq analyses showed that these cells expressed the receptors for these cytokines. Together the 3 cell types form a cytokine circuit in amplifying cytokine responses in LN. The intrinsic cells and infiltrating macrophages also produced other cytokines including M-CSF, SCF, and IL-34 that constituted within the enclosed glomerular space the soluble effector milieu which may mediate cellular damage and proliferation, and cytokine transcriptional and translation regulation. IL-10 and IL-1β were translationally regulated in the glomeruli in the intact kidney in a cell type-specific manner. The production of these 2 cytokines by infiltrating macrophages was undetectable in a visualization system for in situ protein accumulation despite high mRNA expression levels. However, these macrophages in isolated glomeruli which are released from Bowman's capsules produced large amounts of IL-10 and IL-1β. These data reveal the complexity of cytokine regulation, production, and function in the glomerulus and provide a model in which cytokine blocking may be beneficial in LN treatment.
炎症在狼疮性肾炎 (LN) 的发病机制中起关键作用，肾小球内的炎症细胞因子在这一过程中至关重要。然而，对于主要负责各种细胞因子产生和功能的细胞类型的身份，我们知之甚少。我们设计了一种通过共聚焦显微镜可视化肾脏中细胞因子信号的新方法，发现肾小球内细胞因子的产生具有细胞类型特异性，并受翻译调控。在具有慢性肾小球肾炎的狼疮易感 NZM2328 小鼠中，肾小球内的 IL-6、IL-1β 和 TNF-α 分别主要由系膜细胞、足细胞和肾小球浸润的血液来源的巨噬细胞产生。微阵列和 RNASeq 分析表明，这些细胞表达这些细胞因子的受体。这 3 种细胞类型共同构成了 LN 中细胞因子反应放大的细胞因子回路。固有细胞和浸润的巨噬细胞还产生了其他细胞因子，包括 M-CSF、SCF 和 IL-34，它们在封闭的肾小球腔内构成了可溶性效应因子环境，可能介导细胞损伤和增殖，以及细胞因子转录和翻译调控。IL-10 和 IL-1β 在完整肾脏的肾小球中以细胞类型特异性方式进行翻译调控。尽管这些巨噬细胞的 mRNA 表达水平很高，但在用于原位蛋白积累的可视化系统中，其浸润巨噬细胞对这 2 种细胞因子的产生是不可检测的。然而，从鲍曼囊释放的分离肾小球中的这些巨噬细胞会产生大量的 IL-10 和 IL-1β。这些数据揭示了肾小球中细胞因子调控、产生和功能的复杂性，并提供了一个模型，即细胞因子阻断可能有益于 LN 的治疗。
