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Pulmonary Inflammation Triggered by Ricin Toxin Requires Macrophages and IL-1 Signaling¹

Meghan L. Lindauer^*, John Wong^*, Yoichiro Iwakura and Bruce E. Magun^2,*

*Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, OR 97239; and Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Sirokanedai, Minato-ku, Tokyo, Japan

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-1/β^–/– mice. Furthermore, IL1Ra/anakinra cotreatment inhibited ricin-mediated 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.

³Address correspondence and reprint requests to Dr. Bruce Magun, Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail address: magunb{at}ohsu.edu

¹ This work was funded by the National Institutes of Health under Ruth L. Kirschstein National Research Service Award 5-T32-CA106195 from the National Cancer Institute and by National Institutes of Health Grant AI1059335 (to B.E.M.).