TY - JOUR
T1 - S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation
AU - Sprenkeler, Evelien G. G.
AU - Zandstra, Judith
AU - van Kleef, Nadine D.
AU - Goetschalckx, Ines
AU - Verstegen, Bibian
AU - Aarts, Cathelijn E. M.
AU - Janssen, Hans
AU - Tool, Anton T. J.
AU - van Mierlo, Gerard
AU - van Bruggen, Robin
AU - Jongerius, Ilse
AU - Kuijpers, Taco W.
N1 - Funding Information: Funding: This study was partially funded by the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 668303. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8/A9 upon PMA stimulation. Moreover, we purified S100A8/A9 from the cytoplasmic fraction of neutrophils and found that S100A8/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation.
AB - Neutrophils are the most abundant innate immune cells in the circulation and they are the first cells recruited to sites of infection or inflammation. Almost half of the intracellular protein content in neutrophils consists of S100A8 and S100A9, though there has been controversy about their actual localization. Once released extracellularly, these proteins are thought to act as damage-associated molecular patterns (DAMPs), though their mechanism of action is not well understood. These S100 proteins mainly form heterodimers (S100A8/A9, also known as calprotectin) and this heterocomplex is recognized as a useful biomarker for several inflammatory diseases. We observed that S100A8/A9 is highly present in the cytoplasmic fraction of neutrophils and is not part of the granule content. Furthermore, we found that S100A8/A9 was not released in parallel with granular content but upon the formation of neutrophil extracellular traps (NETs). Accordingly, neutrophils of patients with chronic granulomatous disease, who are deficient in phorbol 12-myristate 13-acetate (PMA)-induced NETosis, did not release S100A8/A9 upon PMA stimulation. Moreover, we purified S100A8/A9 from the cytoplasmic fraction of neutrophils and found that S100A8/A9 could induce neutrophil activation, including adhesion and CD11b upregulation, indicating that this DAMP might amplify neutrophil activation.
KW - Calprotectin
KW - MRP8/14
KW - Neutrophil extracellular traps
KW - Neutrophils
KW - S100A8/A9
UR - http://www.scopus.com/inward/record.url?scp=85122677936&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cells11020236
DO - https://doi.org/10.3390/cells11020236
M3 - Article
C2 - 35053354
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 2
M1 - 236
ER -