Impact of macrophages on neutrophils and endothelial cells in the kidney in hemolytic uremic syndrome induced by shiga toxin-producing E-coli

由产志贺毒素（Stx）大肠杆菌（STEC）引起的溶血性尿毒综合征（HUS）是一种无法治愈的食源性疾病，导致严重的健康状况，需要昂贵的和降低生活质量的支持性护理。摄入后，STEC在肠道定植，这些病原体产生的Stx进入循环，损害微血管，特别是肾脏。有新的证据表明，中性粒细胞在STEC-HUS中起着关键作用，这些细胞的丰度增加与临床结果不佳相关。在初步研究中，我们发现STEC-HUS小鼠模型中肾小球内中性粒细胞的活化和积累。我们还注意到致密的肾肾小球周围巨噬细胞网络，表明STEC-HUS期间巨噬细胞和中性粒细胞之间存在串扰。在STEC-HUS中，巨噬细胞的消耗导致体重减轻和肾损伤减少，证明肾巨噬细胞在STEC-HUS中的关键作用。本提案旨在阐明1.巨噬细胞如何应对STEC，2。巨噬细胞调节肾脏微环境的质量，3。巨噬细胞反应的下游效应，特别关注中性粒细胞和4。靶向巨噬细胞和中性粒细胞上的关键分子是否能改善疾病的严重程度。这些实验揭示了STEC-HUS中协调免疫应答的细胞和分子机制。此外，我们阐明了靶向巨噬细胞及其产物或巨噬细胞依赖性中性粒细胞募集是否可能是治愈STEC-HUS的治疗靶点。

Hemolytic uremic syndrome (HUS) caused by shiga-toxin (Stx) producing E.coli (STEC) is an incurable foodborne disease leading to severe health conditions, requiring expensive and life-quality reducing supportive care. After ingestion, STEC colonize the gut and Stx produced by these pathogens traverses into the circulation, damaging the microvasculature, particularly in the kidney. There is emerging evidence for a critical role of neutrophils during STEC-HUS, and increased abundance of these cells is associated with a poor clinical outcome. In a preliminary study we found activation and accumulation of neutrophils within the renal glomerulus in a mouse model of STEC-HUS. We also noted a dense renal periglomerular macrophage network, indicating a crosstalk between macrophages and neutrophils during STEC-HUS. Depletion of macrophages resulted in reduced weight loss and kidney injury in STEC-HUS, demonstrating a crucial role for renal macrophages in STEC-HUS. This proposal aims at elucidating 1. How macrophages respond to STEC, 2. The quality of modulation of the kidney microenvironment by macrophages, 3. The downstream effects of the macrophage-response with a particular focus on neutrophils and 4. Whether targeting the key molecules on macrophages and neutrophils ameliorates disease severity. These experiments unravel the cellular and molecular mechanisms orchestrating the immune response in STEC-HUS. Furthermore, we clarify whether targeting macrophages and their products or macrophage-dependent neutrophil recruitment might be therapeutical targets to cure STEC-HUS.