Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19

Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting self-damage upon transition hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing lung injury and acute respiratory distress syndrome (ARDS) patients with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry–based proteomics transcriptomic correlative analyses as well functional vitro vivo studies dissect how neutrophils contribute the progression severe COVID-19. We identify reinforcing loop both systemic intrinsic IL-8 (CXCL8/IL-8) dysregulation, which initiates perpetuates neutrophil-driven immunopathology. This positive feedback autocrine production leads an activated, prothrombotic phenotype characterized by degranulation extracellular trap (NET) formation. In COVID-19, directly initiate coagulation complement cascade, highlighting link immunothrombotic state observed these patients. Targeting IL-8–CXCR-1/-2 axis interferes this vicious cycle attenuates activation, degranulation, NETosis, release. Finally, show that blocking IL-8–like signaling reduces 2 (SARS-CoV-2) spike protein–induced, human ACE2–dependent pulmonary microthrombosis mice. summary, our data comprehensive insights into activation mechanisms COVID-19 uncover self-sustaining neutrophil–IL-8 promising therapeutic target SARS-CoV-2 infection.