Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines.
Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Christine
C
Schauer
1] Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany. [2] Department of Otorhinolaryngology, Head and Neck Surgery, Section for Experimental Oncology and Nanomedicine (SEON), University Hospital Erlangen, Erlangen, Germany.
Christina
C
Janko
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Luis E
LE
Munoz
1] Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany. [2] Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China.
Yi
Y
Zhao
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Deborah
D
Kienhöfer
Department of Radiation Oncology, University Hospital Erlangen, Erlangen, Germany.
Benjamin
B
Frey
Department of Radiology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
Michael
M
Lell
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Bernhard
B
Manger
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Jürgen
J
Rech
Division of Molecular and Experimental Surgery, Department of Surgery, University of Erlangen Medical Center, Erlangen, Germany.
Elisabeth
E
Naschberger
Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Rikard
R
Holmdahl
Department of Pathology, MVZ of Pathology, Trier, Germany.
Veit
V
Krenn
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Thomas
T
Harrer
1] Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany. [2] Institute of Rheumatology, School of Medicine, University of Belgrade, Belgrade, Serbia.
Ivica
I
Jeremic
Institute of Cell Biology, National Academy of Sciences of Ukraine, Lviv, Ukraine.
Rostyslav
R
Bilyy
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Georg
G
Schett
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Markus
M
Hoffmann
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
Martin
M
Herrmann
D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D006073:Gout / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D016897:Respiratory Burst / Q000187:drug effects; D013582:Synovial Fluid / Q000187:drug effects; D014527:Uric Acid / Q000633:toxicity
D018925:Chemokines; D016207:Cytokines; D014527:Uric Acid