Pulmonary inflammation triggered by ricin toxin requires macrophages and IL-1 signaling

Meghan L. Lindauer, John Wong, Yoichiro Iwakura, Bruce E. Magun

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Ricin is a potent ribotoxin considered to be a potentially dangerous bioterrorist agent due to its wide availability and the possibility of aerosol delivery to human populations. Studies in rodents and nonhuman primates have demonstrated that ricin delivered to the pulmonary system leads to acute lung injury and symptoms resembling acute respiratory distress syndrome. Increasing evidence suggests that the inflammatory effects triggered by ricin are responsible for its lethality. We demonstrated previously that ricin administered to the lungs of mice causes death of pulmonary macrophages and the release of proinflammatory cytokines, suggesting macrophages may be a primary target of ricin. Here we examined the requirement for macrophages in the development of ricin-mediated pulmonary inflammation by employing transgenic (MAFIA) mice that express an inducible gene driven by the c-fms promoter for Fas-mediated apoptosis of macrophages upon injection of a synthetic dimerizer, AP20187. Administration of aerosolized ricin to macrophage-depleted mice led to reduced inflammatory responses, including recruitment of neutrophils, expression of proinflammatory transcripts, and microvascular permeability. When compared with control mice treated with ricin, macrophage-depleted mice treated with ricin displayed a reduction in pulmonary IL-1β. Employing mice deficient in IL-1, we found that ricin-induced inflammatory responses were suppressed, including neutrophilia. Neutrophilia could be restored by co-administering ricin and exogenous IL-1β to IL-1α/β-/- mice. Furthermore, IL1Ra/anakinra cotreatment inhibited ricinmediated inflammatory responses, including recruitment of neutrophils, expression of proinflammatory genes, and histopathology. These data suggest a central role for macrophages and IL-1 signaling in the inflammatory process triggered by ricin.

Original languageEnglish (US)
Pages (from-to)1419-1426
Number of pages8
JournalJournal of Immunology
Volume183
Issue number2
DOIs
StatePublished - Jul 15 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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