title: Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo.
abstract: The innate immune system relies to a great deal on the interaction of pattern recognition receptors with pathogen- or damage-associated molecular pattern molecules. Extracellular histones belong to the latter group and their release has been described to contribute to the induction of systemic inflammatory reactions. However, little is known about their functions in the early immune response to an invading pathogen. Here we show that extracellular histones specifically target monocytes in human blood and this evokes the mobilization of the chemotactic chemokines CXCL9 and CXCL10 from these cells. The chemokine induction involves the toll-like receptor 4/myeloid differentiation factor 2 complex on monocytes, and is under the control of interferon-γ. Consequently, subcutaneous challenge with extracellular histones results in elevated levels of CXCL10 in a murine air pouch model and an influx of leukocytes to the site of injection in a TLR4 dependent manner. When analyzing tissue biopsies from patients with necrotizing fasciitis caused by Streptococcus pyogenes, extracellular histone H4 and CXCL10 are immunostained in necrotic, but not healthy tissue. Collectively, these results show for the first time that extracellular histones have an important function as chemoattractants as their local release triggers the recruitment of immune cells to the site of infection.
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Johannes
authors.initials: J
authors.lastname: Westman
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Praveen
authors.initials: P
authors.lastname: Papareddy
authors.affiliation: Department of Experimental Medical Science, Adaptive Immunity, Biomedical Center, Lund, Sweden.
authors.forename: Madelene W
authors.initials: MW
authors.lastname: Dahlgren
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Chakrakodi
authors.affiliation: Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Smeds
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Adam
authors.initials: A
authors.lastname: Linder
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Department of Experimental Medical Science, Adaptive Immunity, Biomedical Center, Lund, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Johansson-Lindbom
authors.affiliation: Department of Clinical Sciences, Respiratory Medicine & Allergy, Biomedical Center, Lund, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Egesten
authors.affiliation: Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden.
authors.forename: Heiko
authors.initials: H
authors.lastname: Herwald
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000096:biosynthesis* / Q000276:immunology; D054370:Chemokine CXCL9 / Q000096:biosynthesis* / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006657:Histones / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009000:Monocytes / Q000276:immunology; D020349:Surface Plasmon Resonance
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D006657:Histones