Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap–mediated sterile inflammation

• Published in: Blood Vol. 123; no. 16; pp. 2573 - 2584
• Main Authors: Rossaint, Jan, Herter, Jan M., Van Aken, Hugo, Napirei, Markus, Döring, Yvonne, Weber, Christian, Soehnlein, Oliver, Zarbock, Alexander
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.04.2014
• Subjects: Acute Lung Injury - immunology; Acute Lung Injury - metabolism; Animals; Chemokine CCL5 - metabolism; Chemokines - metabolism; Deoxyribonuclease I - genetics; Extracellular Space - metabolism; HSP90 Heat-Shock Proteins; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Integrins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Leukocyte Elastase - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophil Infiltration - genetics; Neutrophils - physiology; Platelet Factor 4 - metabolism; Protein Multimerization; Severity of Illness Index
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-07-516484

There is emerging evidence that neutrophil extracellular traps (NETs) play important roles in inflammatory processes. Here we report that neutrophils have to be simultaneously activated by integrin-mediated outside-in– and G-protein–coupled receptor (GPCR) signaling to induce NET formation in acute lung injury (ALI), which is associated with a high mortality rate in critically ill patients. NETs consist of decondensed chromatin decorated with granular and cytosolic proteins and they can trap extracellular pathogens. The prerequisite for NET formation is the activation of neutrophils and the release of their DNA. In a neutrophil- and platelet-dependent mouse model of ventilator-induced lung injury (VILI), NETs were found in the lung microvasculature, and circulating NET components increased in the plasma. In this model, blocking integrin-mediated outside-in or either GPCR-signaling or heteromerization of platelet chemokines decreased NET formation and lung injury. Targeting NET components by DNAse1 application or neutrophil elastase–deficient mice protected mice from ALI, whereas DNase1−/−/Trap1m/m mice had an aggravated ALI, suggesting that NETs directly influence the severity of ALI. These data suggest that NETs form in the lungs during VILI, contribute to the disease process, and thus may be a promising new direction for the treatment of ALI. •NET formation is required for neutrophil recruitment during sterile inflammation.•Platelet-induced NET formation requires stimulation of neutrophils by platelet chemokines and outside-in signaling via the integrin Mac-1.