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Kaiser, R.* ; Leunig, A.* ; Pekayvaz, K.* ; Popp, O.* ; Joppich, M.* ; Polewka, V.* ; Escaig, R.* ; Anjum, A.* ; Hoffknecht, M.L.* ; Gold, C.* ; Brambs, S.* ; Engel, A.* ; Stockhausen, S.* ; Knottenberg, V.* ; Titova, A.* ; Haji, M.* ; Scherer, C.* ; Muenchhoff, M.* ; Hellmuth, J.C.* ; Saar, K.* ; Schubert, B. ; Hilgendorff, A. ; Schulz, C.* ; Kääb, S.* ; Zimmer, R.* ; Hübner, N.* ; Massberg, S.* ; Mertins, P.* ; Nicolai, L.* ; Stark, K.*

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

JCI insight 6:e150862 (2021)

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Neutrophils provide a critical line of defense in immune responses to various pathogens, but also inflict self-damage upon transition to a hyperactivated, procoagulant state. Recent work has highlighted proinflammatory neutrophil phenotypes contributing to lung injury and acute respiratory distress syndrome (ARDS) in patients suffering from COVID-19. Here, we utilize state-of-the art mass spectrometry-based proteomics, transcriptomic and correlative analyses as well as functional in vitro and in vivo studies to dissect how neutrophils contribute to the progression to severe COVID-19. We identify a reinforcing loop of both systemic and neutrophil intrinsic interleukin-8 (CXCL8/IL-8) dysregulation, which initiates and perpetuates neutrophil-driven immunopathology. This positive feedback loop of systemic and neutrophil autocrine IL-8 production leads to an activated, prothrombotic neutrophil phenotype characterized by degranulation and neutrophil extracellular trap (NET) formation. In severe COVID-19, neutrophils directly initiate the coagulation and complement cascade, highlighting a link to the immunothrombotic state observed in these patients. Targeting the IL-8-CXCR-1/-2 axis interferes with this vicious cycle and attenuates neutrophil activation, degranulation, NETosis, and IL-8 release. Finally, we show that blocking IL-8-like signaling reduces SARS-CoV-2 spike protein-induced, hACE2-dependent pulmonary microthrombosis in mice. In summary, our data provide comprehensive insights into the activation mechanisms of neutrophils in COVID-19 and uncover a self-sustaining neutrophil-IL-8-axis as promising therapeutic target in severe SARS-CoV-2 infection.

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