Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion

Sara Tassi, Sonia Carta, Laura Delfino, Roberta Caorsi, Alberto Martini, Marco Gattorno, Anna Rubartelli

Research output: Contribution to journalArticlepeer-review

Abstract

In healthy monocytes, Toll-like receptor (TLR) engagement induces production of reactive oxygen species (ROS), followed by an antioxidant response involved in IL-1β processing and secretion. Markers of the antioxidant response include intracellular thioredoxin and extracellular release of reduced cysteine. Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases in which Nod-like receptor family pyrin domain-containing 3 (NLRP3) genemutations lead to increased IL-1β secretion. We showin a large cohort of patients that IL-1β secretion by CAPS monocytes is much faster than that by healthy monocytes. This accelerated kinetics is caused by alterations in the basal redox state, as well as in the redox response to TLR triggering displayed by CAPS monocytes. Indeed, unstimulated CAPS monocytes are under a mild oxidative stress, with elevated levels of both ROS and antioxidants. The redox response to LPS is quickened, with early generation of the reducing conditions favoring IL-1β processing and secretion, and then rapidly exhausted. Therefore, secretion of IL-1β is accelerated, but reaches a plateau much earlier than in healthy controls. Pharmacologic inhibition of the redox response hinders IL-1β release, confirming the functional link between redox impairment and altered kinetics of secretion. Monocytes from patients with juvenile idiopathic arthritis display normal kinetics of redox response and IL-1β secretion, excluding a role of chronic inflammation in the alterations observed in CAPS. We conclude that preexisting redox alterations distinct from CAPS monocytes anticipate the pathogen-associated molecular pattern molecule-induced generation of the reducing environment favorable to inflammasome activation and IL-1β secretion.

Original languageEnglish
Pages (from-to)9789-9794
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number21
DOIs
Publication statusPublished - May 25 2010

Keywords

  • Antioxidant response
  • Autoinflammatory diseases
  • Inflammasome
  • Reactive oxygen species
  • Thioredoxin

ASJC Scopus subject areas

  • General

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