title: Radiation exposure induces inflammasome pathway activation in immune cells.
abstract: Radiation exposure induces cell and tissue damage, causing local and systemic inflammatory responses. Because the inflammasome pathway is triggered by cell death and danger-associated molecular patterns, we hypothesized that the inflammasome may signal acute and chronic immune responses to radiation. Using a mouse radiation model, we show that radiation induces a dose-dependent increase in inflammasome activation in macrophages, dendritic cells, NK cells, T cells, and B cells as judged by cleaved caspase-1 detection in cells. Time course analysis showed the appearance of cleaved caspase-1 in cells by day 1 and sustained expression until day 7 after radiation. Also, cells showing inflammasome activation coexpressed the cell surface apoptosis marker annexin V. The role of caspase-1 as a trigger for hematopoietic cell losses after radiation was studied in caspase-1(-/-) mice. We found less radiation-induced cell apoptosis and immune cell loss in caspase-1(-/-) mice than in control mice. Next, we tested whether uric acid might mediate inflammasome activation in cells by treating mice with allopurinol and discovered that allopurinol treatment completely blocked caspase-1 activation in cells. Finally, we demonstrate that radiation-induced caspase-1 activation occurs by a Nod-like receptor family protein 3-independent mechanism because radiation-exposed Nlrp3(-/-) mice showed caspase-1 activation profiles that were indistinguishable from those of wild-type mice. In summary, our data demonstrate that inflammasome activation occurs in many immune cell types following radiation exposure and that allopurinol prevented radiation-induced inflammasome activation. These results suggest that targeting the inflammasome may help control radiation-induced inflammation.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.
authors.forename: Veit M
authors.initials: VM
authors.lastname: Stoecklein
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.
authors.forename: Akinori
authors.initials: A
authors.lastname: Osuka
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.
authors.forename: Shizu
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.
authors.forename: Madeline R
authors.initials: MR
authors.lastname: Lederer
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Wanke-Jellinek
authors.affiliation: Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA 02115 jlederer@rics.bwh.harvard.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Lederer
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics; D016923:Cell Death / Q000276:immunology / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000276:immunology / Q000528:radiation effects; D016207:Cytokines / Q000097:blood; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000528:radiation effects; D007107:Immune System / Q000502:physiology* / Q000528:radiation effects*; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011832:Radiation Injuries / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000528:radiation effects; D014527:Uric Acid / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D014527:Uric Acid; D020170:Caspase 1