GITR gene deletion and gitr-fc soluble protein administration inhibit multiple organ failure induced by zymosan

Maria Galuppo, Giuseppe Nocentini, Emanuela Mazzon, Simona Ronchetti, Emanuela Esposito, Luisa Riccardi, Rosanna Di Paola, Stefano Bruscoli, Carlo Riccardi, Salvatore Cuzzocrea

Research output: Contribution to journalArticlepeer-review

Abstract

Multiple organ dysfunction syndrome (MODS) is a systemic inflammatory event that can result in organ damage, failure, and high risk of mortality. The aim of this study was to evaluate the possible role of glucocorticoid-induced TNFR-related (GITR) on zymosan-induced MODS. Mice were allocated into one GITR knockout (GITR-KO) and two GITR wild-type (GITR-WT) experimental groups. All the animals were treated with zymosan (500 mg/kg, suspended in saline solution, i.p.), and animals of one GITR-WT group received GITR-Fc (6.25 μg/mouse; 3 h after zymosan injection) by mini-osmotic pump. Moreover, three control groups were performed (one GITR-KO and two GITR-WT experimental groups), administering saline instead of zymosan and treating one of the GITR-WT group with GITR-Fc (6.25 μg/mouse; 3 h after saline injection) by mini-osmotic pump. A number of inflammatory parameters such as edema formation, histological damage, adhesion molecules expression, neutrophil infiltration, proinflammatory cytokines, nitrotyrosine, and iNOS production are significantly reduced in GITR-KO as compared with GITR-WT mice as well as in GITR-WT mice treated with GITR-Fc. We here show that GITR plays a role in the modulation of experimental MODS. In particular, we show that genetic inhibition of GITR expression, in GITR-KO mice, or administration of soluble GITR-Fc receptor in GITR-WT mice, reduces inflammation, organ tissue damage, and mortality. Results, while confirming the proinflammatory role of GITR, extend our observations indicating that GITR plays a role in zymosan-induced inflammation and MODS.

Original languageEnglish
Pages (from-to)263-271
Number of pages9
JournalShock
Volume36
Issue number3
DOIs
Publication statusPublished - Sep 2011

Keywords

  • fusion protein
  • Inflammation
  • knockout mice
  • MODS
  • TNFRSF

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Emergency Medicine

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