title: Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor-Alpha Production in Mice after Bone Marrow Transplantation.
abstract: Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α-driven HPS in BMT mice and is effectively treated through TNF-α inhibition.
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan; Department of Chest Surgery, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onai
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ohyagi
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirokawa
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Ubukawa
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Isuzu
authors.initials: I
authors.lastname: Kobayashi
authors.affiliation: Life Science Tokyo Advanced Research Center, Hoshi University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tezuka
authors.affiliation: Department of Chest Surgery, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Minamiya
authors.affiliation: Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohteki
authors.affiliation: Akita University, Akita, Japan. Electronic address: ksawada@doc.med.akita-u.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sawada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D018899:CpG Islands / Q000276:immunology; D000068800:Etanercept / Q000494:pharmacology; D005720:Gamma Rays; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology*; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D014916:Whole-Body Irradiation
chemical_list: D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D007371:Interferon-gamma; D000068800:Etanercept
keywords: Bone marrow transplantation; Cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG-ODN); Hemophagocytic syndrome; IFN-γ; TNF-α