Extracellular Histones Induce Chemokine Production in Whole Blood Ex Vivo and Leukocyte Recruitment In Vivo

PLoS Pathogens

Johannes Westman¹  Adam Linder¹  Praveen Papareddy¹  Emanuel Smeds¹  Matthias Mörgelin¹  Heiko Herwald¹  Arne Egesten²  Bengt Johansson-Lindbom³  Madelene W. Dahlgren³  Anna Norrby-Teglund⁴  Bhavya Chakrakodi⁴ 

[1] Department of Clinical Sciences, Division of Infection Medicine, Biomedical Center, Lund, Sweden;Department of Clinical Sciences, Respiratory Medicine & Allergy, Biomedical Center, Lund, Sweden;Department of Experimental Medical Science, Adaptive Immunity, Biomedical Center, Lund, Sweden;Department of Medicine, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden

关键词: Histones;    Blood;    Chemokines;    Monocytes;    Cytokines;    Blood plasma;    Toll-like receptors;    Enzyme-linked immunoassays;   

DOI  :  10.1371/journal.ppat.1005319

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY