title: Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice.
abstract: The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2(+/-)) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2(-/-)) and wild-type (mCxcr2(+/+)) mice. Acute sepsis-associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis.
authors.affiliation: Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Majlis
authors.initials: M
authors.lastname: Svensson
authors.forename: Manisha
authors.initials: M
authors.lastname: Yadav
authors.forename: Bo
authors.initials: B
authors.lastname: Holmqvist
authors.forename: Nataliya
authors.initials: N
authors.lastname: Lutay
authors.forename: Catharina
authors.initials: C
authors.lastname: Svanborg
authors.forename: Gabriela
authors.initials: G
authors.lastname: Godaly
mesh_terms: D000208:Acute Disease; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D007113:Immunity, Innate / Q000235:genetics; D007668:Kidney / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D020556:Neutrophil Infiltration; D010641:Phenotype; D011704:Pyelonephritis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D014552:Urinary Tract Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D018925:Chemokines; D023063:Receptors, Interleukin-8B