title: IL-1α signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo.
abstract: Legionella pneumophila is an intracellular bacterial pathogen that is the cause of a severe pneumonia in humans called Legionnaires' disease. A key feature of L. pneumophila pathogenesis is the rapid influx of neutrophils into the lungs, which occurs in response to signaling via the IL-1R. Two distinct cytokines, IL-1α and IL-1β, can stimulate the type I IL-1R. IL-1β is produced upon activation of cytosolic sensors called inflammasomes that detect L. pneumophila in vitro and in vivo. Surprisingly, we find no essential role for IL-1β in neutrophil recruitment to the lungs in response to L. pneumophila. Instead, we show that IL-1α is a critical initiator of neutrophil recruitment to the lungs of L. pneumophila-infected mice. We find that neutrophil recruitment in response to virulent L. pneumophila requires the production of IL-1α specifically by hematopoietic cells. In contrast to IL-1β, the innate signaling pathways that lead to the production of IL-1α in response to L. pneumophila remain poorly defined. In particular, although we confirm a role for inflammasomes for initiation of IL-1β signaling in vivo, we find no essential role for inflammasomes in production of IL-1α. Instead, we propose that a novel host pathway, perhaps involving inhibition of host protein synthesis, is responsible for IL-1α production in response to virulent L. pneumophila. Our results establish IL-1α as a critical initiator of the inflammatory response to L. pneumophila in vivo and point to an important role for IL-1α in providing an alternative to inflammasome-mediated immune responses in vivo.
authors.affiliation: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Barry
authors.forename: Mary F
authors.initials: MF
authors.lastname: Fontana
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Portman
authors.forename: Aisling S
authors.initials: AS
authors.lastname: Dugan
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007249:Inflammation / Q000276:immunology*; D053582:Interleukin-1alpha / Q000276:immunology*; D016952:Legionella pneumophila; D007877:Legionnaires' Disease / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D053582:Interleukin-1alpha