Endothelial damage induced by Shiga toxins delivered by neutrophils during transmigration.
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.
Brigotti
Maurizio
M
Dipartimento di Patologia Sperimentale, Università di Bologna, Bologna, Italy. maurizio.brigotti@unibo.it
Tazzari
Pier Luigi
PL
Ravanelli
Elisa
E
Carnicelli
Domenica
D
Barbieri
Stefania
S
Rocchi
Laura
L
Arfilli
Valentina
V
Scavia
Gaia
G
Ricci
Francesca
F
Bontadini
Andrea
A
Alfieri
Roberta R
RR
Petronini
Pier Giorgio
PG
Pecoraro
Carmine
C
Tozzi
Alberto E
AE
Caprioli
Alfredo
A
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*
D016207:Cytokines; D022622:Shiga Toxin 1