PDF(Pubmed)
Abstract：
Urinary tract infection (UTI) commonly afflicts people with diabetes. This augmented infection risk is partly due to deregulated insulin receptor (IR) signaling in the kidney collecting duct. The collecting duct is composed of intercalated cells (ICs) and principal cells (PCs). Evidence suggests that ICs contribute to UTI defenses. Here, we interrogate how IR deletion in ICs impacts antibacterial defenses against uropathogenic Escherichia coli. We also explore how IR deletion affects immune responses in neighboring PCs with intact IR expression. To accomplish this objective, we profile the transcriptomes of IC and PC populations enriched from kidneys of wild-type and IC-specific IR knock-out mice that have increased UTI susceptibility. Transcriptomic analysis demonstrates that IR deletion suppresses IC-integrated stress responses and innate immune defenses. To define how IR shapes these immune defenses, we employ murine and human kidney cultures. When challenged with bacteria, murine ICs and human kidney cells with deregulated IR signaling cannot engage central components of the integrated stress response-including activating transcriptional factor 4 (ATF4). Silencing ATF4 impairs NFkB activation and promotes infection. In turn, NFkB silencing augments infection and suppresses antimicrobial peptide expression. In diabetic mice and people with diabetes, collecting duct cells show reduced IR expression, impaired integrated stress response engagement, and compromised immunity. Collectively, these translational data illustrate how IR orchestrates collecting duct antibacterial responses and the communication between ICs and PCs.
摘要：
尿路感染（UTI）通常会困扰糖尿病患者。这种增加的感染风险部分是由于肾脏集合管中胰岛素受体（IR）信号的失调。收集管由嵌入细胞(IC)和主细胞(PC)组成。证据表明IC有助于UTI防御。这里,我们询问IC中的IR缺失如何影响针对尿路致病性大肠杆菌的抗菌防御。我们还探讨了IR缺失如何影响具有完整IR表达的邻近PC中的免疫应答。为了实现这一目标，我们对UTI易感性增加的野生型和IC特异性IR敲除小鼠的肾脏富集的IC和PC群体的转录组进行了分析.转录组分析表明，IR缺失抑制了IC整合的应激反应和先天免疫防御。为了定义红外如何塑造这些免疫防御，我们使用鼠和人的肾脏培养物。当受到细菌的挑战时，具有去调节的IR信号的鼠IC和人肾细胞不能参与整合应激反应的中心成分，包括激活转录因子4（ATF4）。沉默ATF4损害NFkB活化并促进感染。反过来,NFkB沉默增加感染并抑制抗菌肽表达。在糖尿病小鼠和糖尿病患者中，收集管细胞显示降低的IR表达，综合应激反应参与受损，免疫力受损。总的来说，这些翻译数据说明了IR如何协调收集管道抗菌响应以及IC和PC之间的通信。
