title: High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses.
abstract: Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-κB and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1(-/-) mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1(-/-) mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses.
authors.affiliation: Basic Research Program, Scientific Application and International Corporation–Frederick, Inc, Frederick, Frederick, MD 21702, USA. yangd@mail.nih.gov
authors.forename: De
authors.initials: D
authors.lastname: Yang
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Postnikov
authors.forename: Yana
authors.initials: Y
authors.lastname: Li
authors.forename: Poonam
authors.initials: P
authors.lastname: Tewary
authors.forename: Gonzalo
authors.initials: G
authors.lastname: de la Rosa
authors.forename: Feng
authors.initials: F
authors.lastname: Wei
authors.forename: Dennis
authors.initials: D
authors.lastname: Klinman
authors.forename: Theresa
authors.initials: T
authors.lastname: Gioannini
authors.forename: Jerrold P
authors.initials: JP
authors.lastname: Weiss
authors.forename: Takashi
authors.initials: T
authors.lastname: Furusawa
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D002454:Cell Differentiation; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005260:Female; D057809:HEK293 Cells; D024241:HMGN1 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007109:Immunity / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000941:Antigens; D024241:HMGN1 Protein; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4