title: IL-1α and inflammasome-independent IL-1β promote neutrophil infiltration following alum vaccination.
abstract: Despite its long record of successful use in human vaccines, the mechanisms underlying the immunomodulatory effects of alum are not fully understood. Alum is a potent inducer of interleukin-1 (IL-1) secretion in vitro in dendritic cells and macrophages via Nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome activation. However, the contribution of IL-1 to alum-induced innate and adaptive immune responses is controversial and the role of IL-1α following alum injection has not been addressed. This study shows that IL-1 is dispensable for alum-induced antibody and CD8 T cell responses to ovalbumin. However, IL-1 is essential for neutrophil infiltration into the injection site, while recruitment of inflammatory monocytes and eosinophils is IL-1 independent. Both IL-1α and IL-1β are released at the site of injection and contribute to the neutrophil response. Surprisingly, these effects are NLRP3-inflammasome independent as is the infiltration of other cell populations. However, while NLRP3 and caspase 1 were dispensable, alum-induced IL-1β at the injection site was dependent on the cysteine protease cathepsin S. Overall, these data demonstrate a previously unreported role for cathepsin S in IL-1β secretion, show that inflammasome formation is dispensable for alum-induced innate immunity and reveal that IL-1α and IL-1β are both necessary for alum-induced neutrophil influx in vivo.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Oleszycka
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Hannah B T
authors.initials: HB
authors.lastname: Moran
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Graham A
authors.initials: GA
authors.lastname: Tynan
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Claire H
authors.initials: CH
authors.lastname: Hearnden
authors.affiliation: Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Coutts
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Ireland.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Faculty of Life Sciences, University of Manchester, UK.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Allan
authors.affiliation: School of Pharmacy, Queen's University Belfast, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scott
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.|Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Advanced Materials and BioEngineering Research (AMBER), Trinity College Dublin, Ireland.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D058847:Inflammasomes; D053582:Interleukin-1alpha / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology*; D014611:Vaccination
chemical_list: D000534:Alum Compounds; D058847:Inflammasomes; D053582:Interleukin-1alpha; D053583:Interleukin-1beta
keywords: IL-1; aluminium adjuvant; cathepsin S; inflammasome