Chemokine receptor CCR1 disruption limits renal damage in a murine model of hemolytic uremic syndrome.
Shiga toxin (Stx)-producing Escherichia coli is the main etiological agent that causes hemolytic uremic syndrome (HUS), a microangiopathic disease characterized by hemolytic anemia, thrombocytopenia, and acute renal failure. Although direct cytotoxic effects on endothelial cells by Stx are the primary pathogenic event, there is evidence that indicates the inflammatory response mediated by polymorphonuclear neutrophils and monocytes as the key event during HUS development. Because the chemokine receptor CCR1 participates in the pathogenesis of several renal diseases by orchestrating myeloid cell kidney infiltration, we specifically addressed the contribution of CCR1 in a murine model of HUS. We showed that Stx type 2-treated CCR1(-/-) mice have an increased survival rate associated with less functional and histological renal damage compared with control mice. Stx type 2-triggered neutrophilia and monocytosis and polymorphonuclear neutrophil and monocyte renal infiltration were significantly reduced and delayed in CCR1(-/-) mice compared with control mice. In addition, the increase of the inflammatory cytokines (tumor necrosis factor-α and IL-6) in plasma was delayed in CCR1(-/-) mice compared with control mice. These data demonstrate that CCR1 participates in cell recruitment to the kidney and amplification of the inflammatory response that contributes to HUS development. Blockade of CCR1 could be important to the design of future therapies to restrain the inflammatory response involved in the development of HUS.
Division of Immunology, Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina. Electronic address: mvramos@hematologia.anm.edu.ar.
Maria V
MV
Ramos
Laboratory of Immunity and Infection, INSERM UMRS 945, University of Pierre and Marie Curie, Paris, France.
Constance
C
Auvynet
Laboratory of Immunity and Infection, INSERM UMRS 945, University of Pierre and Marie Curie, Paris, France.
Lucie
L
Poupel
Laboratory of Immunity and Infection, INSERM UMRS 945, University of Pierre and Marie Curie, Paris, France.
Mathieu
M
Rodero
Division of Immunology, Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina.
Maria Pilar
MP
Mejias
Division of Immunology, Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina.
Cecilia A
CA
Panek
Division of Pathology, Institute of Oncologic Investigation, National Academy of Medicine, Buenos Aires, Argentina.
Silvia
S
Vanzulli
Laboratory of Immunity and Infection, INSERM UMRS 945, University of Pierre and Marie Curie, Paris, France.
Christophe
C
Combadiere
Division of Immunology, Institute of Experimental Medicine (IMEX-CONICET), National Academy of Medicine, Buenos Aires, Argentina.
Marina
M
Palermo
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D003401:Creatine / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D022423:Myeloid Cells / Q000502:physiology; D054389:Receptors, CCR1 / Q000172:deficiency / Q000502:physiology*; D022641:Shiga Toxin 2 / Q000633:toxicity*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014508:Urea / Q000378:metabolism
D015850:Interleukin-6; D054389:Receptors, CCR1; D022641:Shiga Toxin 2; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D003401:Creatine