Relevance of neutrophils in the murine model of haemolytic uraemic syndrome: mechanisms involved in Shiga toxin type 2-induced neutrophilia

Departmento de Patologia, Centro de Estudios Oncologicos, Academia Nacional de Medicina, Buenos Aires, ArgentinaSummaryIt has been demonstrated that infections due to Shiga toxins (Stx) producingEscherichia coli are the main cause of the haemolytic uraemic syndrome(HUS). However, the contribution of the inflammatory response in the patho-genesis of the disease has also been well established. Neutrophils (PMN) rep-resent a central component of inflammation during infections, and patientswith high peripheral PMN counts at presentation have a poor prognosis. Themouse model of HUS, by intravenous injection of pure Stx type 2 (Stx2),reproduces human neutrophilia and allows the study of early events in thecourse of Stx2-induced pathophysiological mechanisms. The aim of this studywas to address the contribution of PMN on Stx2 toxicity in a murine model ofHUS, by evaluating the survival and renal damage in mice in which the gran-ulocytic population was depleted. We found that the absence of PMN reducedStx2-induced lethal effects and renal damage. We also investigated the mech-anisms underlying Stx2-induced neutrophilia, studying the influence of Stx2on myelopoyesis, on the emergence of cells from the bone marrow and on thein vivo migration into tissues. Stx2 administration led to an acceleratedrelease of bone marrow cells, which egress at an earlier stage of maturation,together with an increase in the proliferation of myeloid progenitors. More-over, Stx2-treated mice exhibited a lower migratory capacity to a local inflam-matory site. In conclusion, PMN are essential in the pathogenesis of HUS andneutrophilia is not merely an epiphenomenon, but contributes to Stx2-dam-aging mechanism by potentiating Stx2 toxicity.Keywords: depletion, HUS, neutrophilia, PMN, Stx2 Introduction