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

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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.