PT Unknown
AU Lill, J
TI Renal macrophages promote Shiga toxin-induced Hemolytic Uremic Syndrome through TNFa and CXCR2- dependent neutrophil recruitment
PD 07
PY 2021
DI 10.17185/duepublico/74476
LA en
DE Immunology, Macrophages, Enterohemorrhagic E. Coli, Neutrophils, Kidney, Nephrology
AB Enterohaemorrhagic Escherichia coli (EHEC) is a major cause for worldwide epidemics linked to significant organ damage and high mortality. One of the EHEC-associated diseases is hemolytic uremic syndrome (HUS); a rare but devastating disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. While the main cause of HUS is due to ingestion of the Shiga toxin-producing E. coli (STEC), an effective therapeutic intervention is yet to be determined. Several studies have identified neutrophil recruitment to be crucial in both the promotion of STEC-HUS severity and mediation of endothelial injury. Nevertheless, the mechanisms leading to this leukocyte activation and recruitment remain elusive. Additionally, the role of macrophages in STEC-HUS is not fully understood, even though they are the predominant leukocyte population in the healthy kidney. In our study, we elucidated the role of resident kidney macrophages in a preclinical STEC-HUS model and showed a phenotypic and functional macrophage change after disease induction, which promoted neutrophil recruitment. Macrophages produced the inflammatory cytokine tumor necrosis factor a (TNFa) and inhibition of this molecule significantly reduced kidney injury. Furthermore, direct targeting of macrophages via their depletion by the colony-stimulating factor receptor 1 (CSF1R) reduced local TNFa levels and significantly decreased disease severity. In detail, macrophage depletion did not only diminish endothelial damage and thrombocytopenia, but additionally activation of thrombocytes and neutrophils. By microscopy, we showed that recruited neutrophils mainly infiltrated the renal cortex in response to STEC-HUS. Macrophage depletion significantly reduced renal neutrophil infiltration and renal levels of neutrophil-attracting C-X-C motif chemokine 1 and 2 (CXCL1 and CXCL2). Intravital microscopy validated that inhibition of CXCR2, the receptor of CXCL1 and CXCL2, significantly attenuates cortical neutrophil recruitment. In addition, CXCR2 inhibition reduced kidney injury thereby emphasizing the role of renal neutrophil recruitment for STEC-HUS severity. In conclusion, our study demonstrates the pathological role of macrophages in STEC-HUS upon activation and subsequent production of proinflammatory cytokines, which lead to the CXCR2-dependent recruitment of neutrophils contributing to kidney injury. In addition, this study identifies inhibition of TNFa, CXCR2 or direct targeting of macrophages via CSF1R as promising therapeutic approaches to inhibit macrophage-dependent inflammation and kidney injury.
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