Role of S100A8/A9 in Platelet-Neutrophil Complex Formation during Acute Inflammation

Cells. 2022 Dec 6;11(23):3944. doi: 10.3390/cells11233944.


Acute respiratory distress syndrome (ARDS) due to pulmonary infections is associated with high morbidity and mortality. Upon inflammation, the alarmin S100A8/A9 is released and stimulates neutrophil recruitment mainly via binding to Toll-like receptor 4 (TLR4). TLR4 is also expressed on platelets, which modulate the immune response through direct interaction with leukocytes. In a murine model of Klebsiella pneumoniae-induced pulmonary inflammation, global S100A9 deficiency resulted in diminished neutrophil recruitment into the lung alveoli and neutrophil accumulation in the intravascular space, indicating an impaired neutrophil migration. A lack of TLR4 on platelets resulted in reduced neutrophil counts in the whole lung, emphasising the impact of TLR4-mediated platelet activity on neutrophil behaviour. Flow cytometry-based analysis indicated elevated numbers of platelet-neutrophil complexes in the blood of S100A9-/- mice. Intravital microscopy of the murine cremaster muscle confirmed these findings and further indicated a significant increase in neutrophil-platelet complex formation in S100A9-/- mice, which was reversed by administration of the S100A8/A9 tetramer. An in vitro bilayer assay simulated the murine alveolar capillary barrier during inflammation and validated significant differences in transmigration behaviour between wild-type and S100A9-/- neutrophils. This study demonstrates the role of S100A8/A9 during platelet-neutrophil interactions and neutrophil recruitment during pulmonary inflammation.

Keywords: ARDS; MRP8/14; acute inflammation; calprotectin; neutrophils; platelets; platelet–neutrophil complexes.

MeSH terms

  • Alarmins / metabolism
  • Animals
  • Calgranulin A* / metabolism
  • Calgranulin B* / metabolism
  • Inflammation / metabolism
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Neutrophils* / metabolism
  • Pneumonia, Bacterial* / metabolism


  • Alarmins
  • Calgranulin A
  • Calgranulin B
  • S100a8 protein, mouse
  • S100A9 protein, mouse