Platelet shedding of CD40L is regulated by matrix metalloproteinase‐9 in abdominal sepsis

• Published in: Journal of thrombosis and haemostasis Vol. 11; no. 7; pp. 1385 - 1398
• Main Authors: Rahman, M., Zhang, S., Chew, M., Syk, I., Jeppsson, B., Thorlacius, H.
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01-07-2013
• Subjects: Alveoli; Animals; Blood Platelets - enzymology; Cardiac and Cardiovascular Systems; Case-Control Studies; CD40 Ligand - blood; Clinical Medicine; Disease Models, Animal; Humans; Kardiologi; Klinisk medicin; lung; Lung - enzymology; Lung - immunology; Lung Injury - blood; Lung Injury - enzymology; Lung Injury - prevention & control; Male; Matrix Metalloproteinase 9 - blood; Matrix Metalloproteinase 9 - deficiency; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; matrix metalloproteinase‐9; Medical and Health Sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration; neutrophils; Peroxidase - metabolism; Platelet Activation; platelets; Pulmonary Edema - blood; Pulmonary Edema - enzymology; Pulmonary Edema - prevention & control; sepsis; Sepsis - blood; Sepsis - enzymology; Sepsis - immunology; Time Factors; lung; matrix metalloproteinase-9; neutrophils; platelets; sepsis
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.12273

Summary
Background and objectives
Platelet‐derived CD40L is known to regulate neutrophil recruitment and lung damage in sepsis. However, the mechanism regulating shedding of CD40L from activated platelets is not known. We hypothesized that matrix metalloproteinase (MMP)‐9 might cleave surface‐expressed CD40L and regulate pulmonary accumulation of neutrophils in sepsis.
Methods
Abdominal sepsis was induced by cecal ligation and puncture (CLP) in wild‐type and MMP‐9‐deficient mice. Edema formation, CXC chemokine levels, myeloperoxidase levels, neutrophils in the lung and plasma levels of CD40L and MMP‐9 were quantified.
Results
CLP increased plasma levels of MMP‐9 but not MMP‐2. The CLP‐induced decrease in platelet surface CD40L and increase in soluble CD40L levels were significantly attenuated in MMP‐9 gene‐deficient mice. Moreover, pulmonary myeloperoxidase (MPO) activity and neutrophil infiltration in the alveolar space, as well as edema formation and lung injury, were markedly decreased in septic mice lacking MMP‐9. In vitro studies revealed that inhibition of MMP‐9 decreased platelet shedding of CD40L. Moreover, recombinant MMP‐9 was capable of cleaving surface‐expressed CD40L on activated platelets. In human studies, plasma levels of MMP‐9 were significantly increased in patients with septic shock as compared with healthy controls, although MMP‐9 levels did not correlate with organ injury score.
Conclusions
Our novel data propose a role of MMP‐9 in regulating platelet‐dependent infiltration of neutrophils and tissue damage in septic lung injury by controlling CD40L shedding from platelets. We conclude that targeting MMP‐9 may be a useful strategy to limit acute lung injury in abdominal sepsis.