The responses of macrophages in interaction with neutrophils that undergo NETosis.
Neutrophil extracellular traps (NETs) are net-like chromatin fibers decorated with antimicrobial proteins, which are released from dying neutrophils. The death of neutrophils with NET formation is called NETosis. Although NETs play important roles in the innate immunity, especially in the elimination of microbes, the extracellular release of DNA and intra-cytoplasmic/nuclear proteins can, on the other hand, result in diverse adversities to the hosts. Therefore, NETosis is adequately regulated in vivo. Currently, two mechanisms, namely DNase I-dependent digestion and phagocytosis by macrophages, have been shown as such regulatory mechanisms. In this study, we focused on the interaction of macrophages and neutrophils that underwent NETosis. Results demonstrated that macrophages displayed a phenotype-dependent response after degradation of NETs. Several hours after the interaction, M2 macrophages induced a pro-inflammatory response, while M1 macrophages underwent cell death with nuclear decondensation. This nuclear decondensation of M1 macrophages occurred in a peptidylarginine deiminase 4-dependent manner and resulted in a local release of extracellular DNA. Thereafter, M1 macrophages degraded DNA derived from themselves in a caspase-activated DNase-dependent manner resulting in the clearance of extracellular DNA within 24 h. This transient increase and subsequent clearance mechanism of extracellular DNA seems very reasonable in terms of the double-edged sword-like property of NETs. The collective findings demonstrate a novel phenotype- and time-dependent regulation of NETosis by macrophages.
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Daigo
D
Nakazawa
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Haruki
H
Shida
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Yoshihiro
Y
Kusunoki
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Arina
A
Miyoshi
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Saori
S
Nishio
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Utano
U
Tomaru
Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Tatsuya
T
Atsumi
Faculty of Health Sciences, Hokkaido University, Sapporo 0600812, Japan. Electronic address: aishizu@med.hokudai.ac.jp.
Akihiro
A
Ishizu
D017209:Apoptosis; D002450:Cell Communication; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D065206:Extracellular Traps / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D020543:Proteome; D040901:Proteomics / Q000379:methods
D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D020543:Proteome; D004247:DNA
Extracellular DNA; Macrophages; NETosis; Neutrophil extracellular traps