title: The lectin like domain of thrombomodulin is involved in the defence against pyelonephritis.
abstract: Pyelonephritis, a common complication of urinary tract infections, is frequently associated with kidney scarring and may lead to end-stage renal disease. During bacterial infections inflammatory and coagulation pathways and their mutual interaction are playing pivotal roles in the host response. Given that thrombomodulin (TM) is crucially involved in the interplay between coagulation and inflammation, we aimed to investigate the roles of its EGF and lectin-like domains in inflammation during acute pyelonephritis. Indeed, the EGF-like and the lectin-like domains of TM, are especially known to orchestrate inflammation and coagulation in different ways. Acute pyelonephritis was induced by intravesical inoculation of 1 × 10(8) CFU of uropathogenic Escherichia coli in two strains of TM transgenic mice. TM(pro/pro) mice carry a mutation in the EGF-like domain making them unable to activate protein C, an anticoagulant and anti-inflammatory protein. TM(LeD/LeD) mice lack the lectin-like domain of TM, which is critical for its anti-inflammatory and cytoprotective properties. Mice were sacrificed 24 and 48 h after inoculation. Bacterial loads, the immune response and the activation of coagulation were evaluated in the kidney and the bladder. TM(LeD/LeD) mice showed elevated bacterial load in bladder and kidneys compared to WT mice, whereas TM(pro/pro) had similar bacterial load as WT mice. TM(LeD/LeD) mice displayed a reduced local production of pro-inflammatory cytokines and neutrophil renal infiltration. Activation of coagulation was comparable in TM(LeD/LeD) and WT mice. From these data, we conclude that the lectin-like domain of thrombomodulin is critically involved in host defence against E. coli induced acute pyelonephritis.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: j.j.roelofs@amc.uva.nl.
authors.forename: Lionel
authors.initials: L
authors.lastname: Lattenist
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Teske
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Nike
authors.initials: N
authors.lastname: Claessen
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Centre for Blood Research, Life Sciences Institute, Division of Haematology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000472:pathogenicity; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation; D007668:Kidney / Q000276:immunology / Q000382:microbiology; D037102:Lectins / Q000737:chemistry*; D007962:Leukocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D011704:Pyelonephritis / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D018180:Thrombomodulin / Q000737:chemistry*; D001743:Urinary Bladder / Q000382:microbiology
chemical_list: D016207:Cytokines; D037102:Lectins; D018180:Thrombomodulin