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10.1172/jci.insight.150862 http://scihub22266oqcxt.onion/10.1172/jci.insight.150862 34403366!8492337!34403366     free     free     free Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       JCI+Insight 2021 ; 6 (18): ä Nephropedia Template TP {{tp|p=34403366|t=2021. Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19 |pdf=|usr=}}{{34403366}} gab.com Text Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19 JO: JCI Insight http://www.kidney.de/pget.php?&tw=1&pmid=34403366 #FOAvip Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting 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 with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and 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 IL-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 severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-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 a promising therapeutic target in severe SARS-CoV-2 infection. Twit Text FOAVip Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19 ????JCI Insight http://www.kidney.de/pget.php?&tw=1&pmid=34403366 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34403366 #FOAvip English Wikipedia <ref>{{Cite pmid|34403366}}</ref> Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype in severe COVID-19 #MMPMID34403366 Kaiser R; Leunig A; Pekayvaz K; Popp O; Joppich M; Polewka V; Escaig R; Anjum A; Hoffknecht ML; Gold C; Brambs S; Engel A; Stockhausen S; Knottenberg V; Titova A; Haji M; Scherer C; Muenchhoff M; Hellmuth JC; Saar K; Schubert B; Hilgendorff A; Schulz C; Kaab S; Zimmer R; Hubner N; Massberg S; Mertins P; Nicolai L; Stark K JCI Insight 2021[Sep]; 6 (18): ä PMID34403366show ga Neutrophils provide a critical line of defense in immune responses to various pathogens, inflicting 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 with coronavirus disease 2019 (COVID-19). Here, we use state-of-the art mass spectrometry-based proteomics and 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 IL-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 severe acute respiratory distress syndrome of coronavirus 2 (SARS-CoV-2) spike protein-induced, human ACE2-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 a promising therapeutic target in severe SARS-CoV-2 infection. |*SARS-CoV-2[MESH] |Animals[MESH] |COVID-19/complications/*metabolism/pathology[MESH] |Humans[MESH] |Interleukin-8/*metabolism[MESH] |Lung/*immunology/pathology[MESH] |Mice[MESH] |Neutrophil Activation[MESH] |Neutrophils/*immunology/pathology[MESH] |Phenotype[MESH]Self-sustaining IL-8 loops drive a prothrombotic neutrophil phenotype (epmc).pdf DeepDyve Pubget Overpricing