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S100A9 induces reactive oxygen species-dependent formation of neutrophil extracellular traps in abdominal sepsis

Du, Feifei LU ; Ding, Zhiyi LU ; Rönnow, Carl-Fredrik LU ; Rahman, Milladur LU orcid ; Schiopu, Alexandru LU and Thorlacius, Henrik LU (2022) In Experimental Cell Research 421(2).
Abstract

Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes... (More)

Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes in S100A9-stimulated neutrophils. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Administration of the S100A9 inhibitor ABR-238901 decreased CLP-induced formation of NETs in lungs and DNA-histone complexes in plasma. In addition, transmission electron microscopy revealed that S100A9 was abundantly expressed on NETs in the lungs in CLP mice. By use of intravital microscopy, we found that local injection of NETs increased leukocyte adhesion and migration in the mouse cremaster muscle microvasculature. Notably, treatment with ABR-238901 attenuated NET-induced leukocyte adhesion and extravasation in the cremaster muscle, suggesting that NET-associated S100A9 promotes leukocyte recruitment in vivo. Taken together, these novel findings suggest that S100A9 triggers ROS-dependent formation of NETs via TLR4 and RAGE signaling in neutrophils. Moreover, S100A9 regulates both formation of NETs and NET-induced leukocyte recruitment in vivo. Thus, targeting S100A9 might be useful to ameliorate lung damage in abdominal sepsis.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Male, Mice, Animals, Extracellular Traps, Reactive Oxygen Species, Toll-Like Receptor 4, Mice, Inbred C57BL, Histones, Sepsis/pathology, Neutrophils/pathology, Calgranulin B
in
Experimental Cell Research
volume
421
issue
2
article number
113405
publisher
Academic Press
external identifiers
  • scopus:85141324852
  • pmid:36328195
ISSN
1090-2422
DOI
10.1016/j.yexcr.2022.113405
language
English
LU publication?
yes
additional info
Copyright © 2022. Published by Elsevier Inc.
id
5ad529f1-c612-4706-91c0-45698d08630d
date added to LUP
2022-11-30 12:40:07
date last changed
2024-06-13 02:51:15
@article{5ad529f1-c612-4706-91c0-45698d08630d,
  abstract     = {{<p>Recent evidence suggests that targeting S100A9 reduces pathological inflammation in abdominal sepsis. Herein, we investigated the role of S100A9 in neutrophil extracellular trap (NET) formation in septic lung damage. NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Stimulation of isolated mouse bone marrow-derived neutrophils with S100A9 triggered formation of NETs. Blocking TLR4 and RAGE reduced S100A9-induced generation of NETs and DNA-histone complexes. Moreover, S100A9 challenge increased generation of reactive oxygen species (ROS) in bone marrow neutrophils. Co-incubation with the NADPH oxidase inhibitor not only decreased ROS formation but also attenuated induction of DNA-histone complexes in S100A9-stimulated neutrophils. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6 mice. Administration of the S100A9 inhibitor ABR-238901 decreased CLP-induced formation of NETs in lungs and DNA-histone complexes in plasma. In addition, transmission electron microscopy revealed that S100A9 was abundantly expressed on NETs in the lungs in CLP mice. By use of intravital microscopy, we found that local injection of NETs increased leukocyte adhesion and migration in the mouse cremaster muscle microvasculature. Notably, treatment with ABR-238901 attenuated NET-induced leukocyte adhesion and extravasation in the cremaster muscle, suggesting that NET-associated S100A9 promotes leukocyte recruitment in vivo. Taken together, these novel findings suggest that S100A9 triggers ROS-dependent formation of NETs via TLR4 and RAGE signaling in neutrophils. Moreover, S100A9 regulates both formation of NETs and NET-induced leukocyte recruitment in vivo. Thus, targeting S100A9 might be useful to ameliorate lung damage in abdominal sepsis.</p>}},
  author       = {{Du, Feifei and Ding, Zhiyi and Rönnow, Carl-Fredrik and Rahman, Milladur and Schiopu, Alexandru and Thorlacius, Henrik}},
  issn         = {{1090-2422}},
  keywords     = {{Male; Mice; Animals; Extracellular Traps; Reactive Oxygen Species; Toll-Like Receptor 4; Mice, Inbred C57BL; Histones; Sepsis/pathology; Neutrophils/pathology; Calgranulin B}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{2}},
  publisher    = {{Academic Press}},
  series       = {{Experimental Cell Research}},
  title        = {{S100A9 induces reactive oxygen species-dependent formation of neutrophil extracellular traps in abdominal sepsis}},
  url          = {{http://dx.doi.org/10.1016/j.yexcr.2022.113405}},
  doi          = {{10.1016/j.yexcr.2022.113405}},
  volume       = {{421}},
  year         = {{2022}},
}