Involvement of the fractalkine pathway in the pathogenesis of childhood hemolytic uremic syndrome.
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.
Ramos
María Victoria
MV
Division of Immunology, Institute of Hematological Investigations, Academia Nacional de Medicina, Buenos Aires, Argentina.
Fernández
Gabriela C
GC
Patey
Natasha
N
Schierloh
Pablo
P
Exeni
Ramón
R
Grimoldi
Irene
I
Vallejo
Graciela
G
Elías-Costa
Christian
C
Del Carmen Sasiain
Maria
M
Trachtman
Howard
H
Combadière
Christophe
C
Proulx
François
F
Palermo
Marina S
MS
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
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