CXCL1/KC and CXCL2/MIP-2 Are Critical Effectors and Potential Targets for Therapy of Escherichia coli O157:H7-Associated Renal Inflammation

• Published in: The American journal of pathology Vol. 170; no. 2; pp. 526 - 537
• Main Authors: Roche, James K, Keepers, Tiffany R, Gross, Lisa K, Seaner, Regina M, Obrig, Tom G
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2007; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Cell Movement - drug effects; Chemokine CXCL1; Chemokine CXCL2; Chemokines - biosynthesis; Chemokines, CXC - biosynthesis; Escherichia coli; Escherichia coli Infections - chemically induced; Escherichia coli Infections - metabolism; Escherichia coli Infections - pathology; Escherichia coli O157; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - microbiology; Inflammation - pathology; Kidney Glomerulus - metabolism; Kidney Glomerulus - microbiology; Kidney Glomerulus - pathology; Lipopolysaccharides - toxicity; Male; Mice; Nephritis - chemically induced; Nephritis - metabolism; Nephritis - microbiology; Nephritis - pathology; Neutrophil Infiltration; Neutrophils - metabolism; Pathology; Regular; Shiga Toxin 2 - toxicity
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.060366

Neutrophilia is a characteristic of hemolytic uremic syndrome caused by Shiga toxin (Stx2)-producing Escherichia coli . However, the role of neutrophils in the toxin-induced renal injury occurring in enterohemorrhagic E. coli infection remains undefined. We report the trafficking of neutrophils to the kidney of C57BL/6 mice throughout a 72-hour time course after challenge with purified E. coli Stx2 and lipopolysaccharide (LPS). Increased neutrophils were observed in the renal cortex, particularly within the glomeruli where a more than fourfold increase in neutrophils was noted within 2 hours after challenge. Using microarray analysis, an increased number of transcripts for chemoattractants CXCL1/KC (69-fold at 2 hours) and CXCL2/MIP-2 (29-fold at 2 hours) were detected. Ribonuclease protection assays, Northern blotting, enzyme-linked immunosorbent assay, and immunohistochemistry confirmed microarray results, showing that both chemokines were expressed only on the immediate periglomerular epithelium and that these events coincided with neutrophil invasion of glomeruli. Co-administration of Stx2 with LPS enhanced and prolonged the KC and MIP-2 host response (RNA and protein) induced by LPS alone. Immunoneutralization in vivo of CXCL1/KC and CXCL2/MIP-2 abrogated neutrophil migration into glomeruli by 85%. These data define the molecular basis for neutrophil migration into the kidney after exposure to virulence factors of Shiga toxin-producing E. coli O157:H7.