title: Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity.
abstract: To understand more about how the body recognizes alum we characterized the early innate and adaptive responses in mice injected with the adjuvant. Within hours of exposure, alum induces a type 2 innate response characterized by an influx of eosinophils, monocytes, neutrophils, DCs, NK cells and NKT cells. In addition, at least 13 cytokines and chemokines are produced within 4 h of injection including IL-1beta and IL-5. Optimal production of some of these, including IL-1beta, depends upon both macrophages and mast cells, whereas production of others, such as IL-5, depends on mast cells only, suggesting that both of these cell types can detect alum. Alum induces eosinophil accumulation partly through the production of mast cell derived IL-5 and histamine. Alum greatly enhances priming of endogenous CD4 and CD8 T cells independently of mast cells, macrophages, and of eosinophils. In addition, Ab levels and Th2 bias was similar in the absence of these cells. We found that the inflammation induced by alum was unchanged in caspase-1-deficient mice, which cannot produce IL-1beta. Furthermore, endogenous CD4 and CD8 T cell responses, Ab responses and the Th2 bias were also not impacted by the absence of caspase-1 or NLRP3. These data suggest that activation of the inflammasome and the type 2 innate response orchestrated by macrophages and mast cells in vivo are not required for adjuvant effect of alum on endogenous T and B cell responses.
authors.affiliation: Howard Hughes Medical Institute, Denver, CO 80206, USA.
authors.forename: Amy S
authors.initials: AS
authors.lastname: McKee
authors.forename: Michael W
authors.initials: MW
authors.lastname: Munks
authors.forename: Megan K L
authors.initials: MK
authors.lastname: MacLeod
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Fleenor
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: John W
authors.initials: JW
authors.lastname: Kappler
authors.forename: Philippa
authors.initials: P
authors.lastname: Marrack
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D015374:Biosensing Techniques; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects*; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000145:classification / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D002352:Carrier Proteins; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C041524:aluminum sulfate; D020170:Caspase 1