title: Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation.
abstract: 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(-/-)/Trap1(m/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.
authors: Department of Anaesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany;
authors: Jan
authors: J
authors: Rossaint
authors: Jan M
authors: JM
authors: Herter
authors: Hugo
authors: H
authors: Van Aken
authors: Markus
authors: M
authors: Napirei
authors: Yvonne
authors: Y
authors: Döring
authors: Christian
authors: C
authors: Weber
authors: Oliver
authors: O
authors: Soehnlein
authors: Alexander
authors: A
authors: Zarbock
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism; D000818:Animals; D018946:Chemokine CCL5 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D003850:Deoxyribonuclease I / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D019272:Leukocyte Elastase / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D009504:Neutrophils / Q000502:physiology*; D010978:Platelet Factor 4 / Q000378:metabolism; D055503:Protein Multimerization; D012720:Severity of Illness Index
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D018925:Chemokines; D018841:HSP90 Heat-Shock Proteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; C547760:TRAP-1 protein, mouse; D010978:Platelet Factor 4; D003850:Deoxyribonuclease I; D019272:Leukocyte Elastase