PMNs (neutrophils) form NETs in response to microbial tissue invasion and tissue damage. 2, 3 NETs are extracellular lattices of decondensed chromatin decorated with antimicrobial factors that trap and kill bacteria and fungi. Discovery of this potent and essential activity of neutrophils has reinvigorated the study of innate immunity and led to significant new discoveries regarding the mechanisms regulating NET formation and their importance in preventing overwhelming infections. Yet, a darker side of NET formation exists, with dysregulated NET formation now suggested as a pathogenic mechanism in autoimmune disorders and other inflammatory syndromes. 4 The current and salient question regarding NET formation is therefore: Do NETs heal or harm? The clear answer is: Yes! In this issue of Blood, Rossaint and colleagues provide new insights into the mechanism through which activated platelets signal to PMNs and trigger NET formation. 1

The key new findings are that dysregulated NET formation participates in the pathogenesis associated with sterile inflammatory syndromes such as ventilator-induced lung injury (VILI) and that simultaneous engagement of G-protein coupled receptors (GPCR) and Mac-1 by the platelet-derived CCL5/CXCL4 heterodimer and ab 2-integrin ligand, respectively, is required for robust NET formation in this model. The investigators used a physiologically relevant in vivo model of VILI and elegant in vitro experiments with human platelets and PMNs to make these discoveries, and their observations extend our information base on the biology of NET formation and the complexity of their activities in preclinical models.