title: Fragments of genomic DNA released by injured cells activate innate immunity and suppress endocrine function in the thyroid.
abstract: Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines. Molecules necessary for antigen processing and presentation to lymphocytes are also induced in thyroid cells by injury. dsDNA strongly suppressed the expression of sodium/iodide symporter and radioiodine uptake. To identify molecules responsible for sensing cytosolic dsDNA, we directly identified the cellular proteins that bound a dsDNA Sepharose column by mass spectrometry. Our analysis identified histone H2B, which was previously demonstrated to be an essential factor that mediates the activation of innate immunity induced by dsDNA. Knockdown of histone H2B using specific small interfering RNA abolished cell injury-induced innate immune activation and increased sodium/iodide symporter expression. These results indicate that genomic DNA fragments released by cell injury are recognized by extrachromosomal histone H2B, which results in the activation of genes involved in both innate and acquired immune responses in thyroid cells and suppression of thyroid function. These results suggest that sterile thyroid injury, in the absence of infection, may be sufficient to trigger autoimmune reaction and to induce thyroid dysfunction.
authors.affiliation: Laboratory of Molecular Diagnostics, Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aoba-cho, Higashimurayama, Tokyo 189-0002, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tanigawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Akama
authors.forename: Huhehasi
authors.initials: H
authors.lastname: Wu
authors.forename: Mariko
authors.initials: M
authors.lastname: Sue
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshihara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishido
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Takeshita
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hirano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sakai
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ishii
authors.forename: Koichi
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D013961:Thyroid Gland / Q000276:immunology* / Q000378:metabolism*