title: Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration.
abstract: The endothelial damage induced by Stx represents the main pathogenic event in the HUS associated with STEC infections in humans. Stx, released in the gut by bacteria, enter the bloodstream and are targeted to renal endothelia. The role of PMN as a toxin carrier has been the object of controversy. In this paper, we confirm the binding of Stx1 to PMN, also showing its degranulating effects on full-loaded leukocytes, and support the carrier role of PMN by using a two-chamber transmigration device, in which PMN, loaded in vitro with different amounts of Stx1, transmigrated through confluent monolayers of endothelial cells, mimicking the toxin-induced renal endothelial injury. Stx1 was transferred during PMN transmigration, impairing protein synthesis and triggering production of proinflammatory cytokines in endothelial cells. PMN, carrying low toxin amounts, induced the release of high levels of cytokines in viable endothelial cells, whereas cytokine production was blocked in cells challenged with PMN fully loaded with Stx as a result of an almost total impairment of translation and of the activation of the apoptotic program. In agreement with previous unexplained observations in animal models, the results obtained with our experimental setting suggest that a self-amplifying circle triggered by low doses of toxin may lead to the production of proinflammatory mediators of renal damage in HUS.
authors.affiliation: Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy. maurizio.brigotti@unibo.it
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brigotti
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Tazzari
authors.forename: Elisa
authors.initials: E
authors.lastname: Ravanelli
authors.forename: Domenica
authors.initials: D
authors.lastname: Carnicelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Barbieri
authors.forename: Laura
authors.initials: L
authors.lastname: Rocchi
authors.forename: Valentina
authors.initials: V
authors.lastname: Arfilli
authors.forename: Gaia
authors.initials: G
authors.lastname: Scavia
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Andrea
authors.initials: A
authors.lastname: Bontadini
authors.forename: Roberta R
authors.initials: RR
authors.lastname: Alfieri
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Petronini
authors.forename: Carmine
authors.initials: C
authors.lastname: Pecoraro
authors.forename: Alberto E
authors.initials: AE
authors.lastname: Tozzi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Caprioli
mesh_terms: D015550:Cell Degranulation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects*; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology; D006801:Humans; D009504:Neutrophils / Q000502:physiology*; D022622:Shiga Toxin 1 / Q000378:metabolism / Q000633:toxicity*
chemical_list: D016207:Cytokines; D022622:Shiga Toxin 1