Tissue-resident macrophages mediate neutrophil recruitment and kidney injury in shiga toxin-induced hemolytic uremic syndrome.

Abstract

Enterohaemorrhagic E. coli cause major epidemics worldwide with significant organ damage and very high percentages of death. Due to the ability of enterohaemorrhagic E. coli to produce shiga toxin these bacteria damage the kidney leading to the hemolytic uremic syndrome. A therapy against this serious kidney disease has not been developed yet and the impact and mechanism of leukocyte activation and recruitment are unclear. Tissue-resident macrophages represent the main leukocyte population in the healthy kidney, but the role of this important cell population in shiga toxin-producing E. coli-hemolytic uremic syndrome is incompletely understood. Using state of the art microscopy and mass spectrometry imaging, our preclinical study demonstrated a phenotypic and functional switch of tissue-resident macrophages after disease induction in mice. Kidney macrophages produced the inflammatory molecule TNFα and depletion of tissue-resident macrophages via the CSF1 receptor abolished TNFα levels in the kidney and significantly diminished disease severity. Furthermore, macrophage depletion did not only attenuate endothelial damage and thrombocytopenia, but also activation of thrombocytes and neutrophils. Moreover, we observed that neutrophils infiltrated the kidney cortex and depletion of macrophages significantly reduced the recruitment of neutrophils and expression of the neutrophil-attracting chemokines CXCL1 and CXCL2. Intravital microscopy revealed that inhibition of CXCR2, the receptor for CXCL1 and CXCL2, significantly reduced the infiltration of neutrophils and reduced kidney injury. Thus, our study shows activation of tissue-resident macrophages during shiga toxin-producing E. coli-hemolytic uremic syndrome leading to the production of disease-promoting TNFα and CXCR2-dependent recruitment of neutrophils.

• Authors: Julia K Lill, Stephanie Thiebes, Judith-Mira Pohl, Jenny Bottek, Nirojah Subramaniam, Robin Christ, Camille Soun, Faikah Gueler, Denise Zwanziger, Franziska Hoffmann, Ferdinand von Eggeling, Thilo Bracht, Barbara Sitek, Michael J Hickey, Oliver Hofnagel, Daniel R Engel
• Journal: Kidney international (Kidney Int) Vol. 100 Issue 2 Pg. 349-363 (08 2021) ISSN: 1523-1755 [Electronic] United States
• PMID: 33930412 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 International Society of Nephrology. All rights reserved.

Chemical References

• Shiga Toxin

Topics

• Animals
• Escherichia coli
• Hemolytic-Uremic Syndrome
• Kidney
• Macrophages
• Mice
• Neutrophil Infiltration
• Shiga Toxin