title: Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo.
abstract: IL-1R activation is required for neutrophil recruitment in an effective innate immune response against Staphylococcus aureus infection. In this study, we investigated the mechanism of IL-1R activation in vivo in a model of S. aureus infection. In response to a S. aureus cutaneous challenge, mice deficient in IL-1beta, IL-1alpha/IL-1beta, but not IL-1alpha, developed larger lesions with higher bacterial counts and had decreased neutrophil recruitment compared with wild-type mice. Neutrophil recruitment and bacterial clearance required IL-1beta expression by bone marrow (BM)-derived cells and not by non-BM-derived resident cells. In addition, mice deficient in the inflammasome component apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) had the same defects in neutrophil recruitment and host defense as IL-1beta-deficient mice, demonstrating an essential role for the inflammasome in mediating the production of active IL-1beta to promote neutrophil recruitment in host defense against S. aureus. This finding was further supported by the ability of recombinant active IL-1beta to control the infection and promote bacterial clearance in IL-1beta-deficient mice. These studies define a key host defense circuit where inflammasome-mediated IL-1beta production by BM-derived cells signals IL-1R on non-BM-derived resident cells to activate neutrophil recruitment in the innate immune response against S. aureus in vivo.
authors.affiliation: Division of Dermatology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.forename: Eric M
authors.initials: EM
authors.lastname: Pietras
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Uricchio
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hirano
authors.forename: Shyam
authors.initials: S
authors.lastname: Rao
authors.forename: Heping
authors.initials: H
authors.lastname: Lin
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Ambrose L
authors.initials: AL
authors.lastname: Cheung
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1