title: Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome.
abstract: Thrombotic microangiopathy and acute renal failure are cardinal features of postdiarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx) through the interaction with its globotriaosyl ceramide receptor. However, inflammatory processes contribute to the pathogenesis of HUS by sensitizing cells to Stx fractalkine (FKN), a CX(3)C transmembrane chemokine expressed on epithelial and endothelial cells upon activation, is involved in the selective migration and adhesion of specific leukocyte subsets to tissues. Here, we demonstrated a selective depletion of circulating mononuclear leukocytes expressing the receptor for FKN (CX(3)CR1) in patients with HUS. We found a unique phenotype in children with HUS distinct from that seen in healthy, uremic, or infected controls, in which monocytes lost CX(3)CR1, down-modulated CD62L, and increased CD16. In addition, the CD56(dim) natural killer (NK) subpopulation was decreased, leading to an altered peripheral CD56(dim)/CD56(bright) ratio from 10.0 to 4.5. It is noteworthy that a negative correlation existed between the percentage of circulating CX(3)CR1(+) leukocytes and the severity of renal failure. Finally, CX(3)CR1(+) leukocytes were observed in renal biopsies from patients with HUS. We suggest that the interaction of CX(3)CR1(+) cells with FKN present on activated endothelial cells may contribute to renal injury in HUS.
authors.affiliation: Division of Immunology, Institute of Hematological Investigations, Academia Nacional de Medicina, Buenos Aires, Argentina.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Ramos
authors.forename: Gabriela C
authors.initials: GC
authors.lastname: Fernández
authors.forename: Natasha
authors.initials: N
authors.lastname: Patey
authors.forename: Pablo
authors.initials: P
authors.lastname: Schierloh
authors.forename: Ramón
authors.initials: R
authors.lastname: Exeni
authors.forename: Irene
authors.initials: I
authors.lastname: Grimoldi
authors.forename: Graciela
authors.initials: G
authors.lastname: Vallejo
authors.forename: Christian
authors.initials: C
authors.lastname: Elías-Costa
authors.forename: Maria
authors.initials: M
authors.lastname: Del Carmen Sasiain
authors.forename: Howard
authors.initials: H
authors.lastname: Trachtman
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadière
authors.forename: François
authors.initials: F
authors.lastname: Proulx
authors.forename: Marina S
authors.initials: MS
authors.lastname: Palermo
mesh_terms: D001706:Biopsy; D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000378:metabolism*; D002675:Child, Preschool; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D019041:L-Selectin