Chemokine receptor CCR1 disruption partially protects from renal damage in a murine model of Hemolytic Uremic Syndrome.

RAMOS, MARIA VICTORIA; AUVYNET, CONSTANCE; POUPEL, LUCIE; PANEK, ANALIA CECILIA; MEJIAS, P; VANZULLI, SILVIA; COMBADIERE, CHRISTOPHE; PALERMO, MARINA SANDRA

Beaver Run Resort, Breckenridge, Colorado

Congreso; Chemokines and Leukocyte Trafficking in Homeostasis and Inflammatio. Keystone Symposia; 2012

Keystone Symposia on Molecular and Celullar Biology

Chemokine receptor CCR1 disruption partially protects from renal damage in a murine model of Hemolytic Uremic Syndrome. 1Ramos,  MV;  2Auvynet, C; 2Poupel, L; 1Panek, CA;  1Mejias,  MP; 1Vanzulli, S; 2Combadiere, C ; 1Palermo, MS. 1Laboratorio de Inmunologia,  Academia Nacional de Medicina, Buenos Aires, Argentina. 2 Inserm UMR-S 945 et UPMC, Laboratoire d´Immunité et Infection, Paris, France. Hemolytic Uremic Syndrome (HUS), a microangiophatic disease characterized by acute renal failure, is caused by Shiga toxin (Stx)-producing Escherichia coli (STEC). Although Stx cytotoxic effect on endothelial cells is the primary pathogenic event, the inflammatory response mediated by leukocytes can increase tissue injury during HUS development. In this work, we show that upon Stx type 2 (Stx2) challenge, CCR1-/- mice have an increased survival rate (72±17 % for CCR1-/-compared to 12±8% for control mice,p<0.01) associated with less renal damage compared to control mice (wt). Stx2-triggered neutrophilia and renal PMN infiltration were reduced and delayed in CCR1-/- mice compared to wt mice. Concomitantly, the increase of plasmatic inflammatory cytokines TNF-a and IL-6 was delayed in CCR1-/- mice indicating that global inflammatory response was altered in CCR1-/- mice. To determine if CCR1-mediated effects were mediated by through hematopoietic and/or stromal cells, wt and CCR1-/- mice were irradiated and reconstituted with CCR1+/+ (wt) or CCR1–/– bone marrow cells. No differences in Stx2 induced mortality were observed in wt mice reconstituted with either CCR1-/- and wt bone marrow indicating CCR1-deficient hematopoietic compartment is not sufficient to provide protection to wt mice. In addition,   survival after Stx2 injection were improved on irradiated CCR1-/- mice reconstituted with either wt or CCR1 bone marrow indicating that CCR1-proficient  hematopoietic compartment does not interfere with mice survival. Our results demonstrate that CCR1 participates in the myeloid cell recruitment and in the amplification of the renal inflammatory response contributing to HUS development. Furthermore, the irradiation/reconstitution experiments indicate a critical role for nonhematopoietic CCR1+/+ cells in Stx2-triggered damage and suggest a novel role of CCR1 in HUS. These findings might provide tools to reduce Stx2-induced damage after STEC infection. Grant acknowledgments to PICT 08/417, ANR- 08-MNPS -003, LSHB-CT-2005-518167.