Patients with COVID-19 in the dark-NETs of neutrophils

Maximilian Ackermann; Hans Joachim Anders; Rostyslav Bilyy; Gary L. Bowlin; Christoph Daniel; Rebecca De Lorenzo; Mikala Egeblad; Timo Henneck; Andrés Hidalgo; Markus Hoffmann; Bettina Hohberger; Yogendra Kanthi; Mariana J. Kaplan; Jason S. Knight; Jasmin Knopf; Elzbieta Kolaczkowska; Paul Kubes; Moritz Leppkes; Aparna Mahajan; Angelo A. Manfredi; Christian Maueröder; Norma Maugeri; Ioannis Mitroulis; Luis E. Muñoz; Teluguakula Narasaraju; Elisabeth Naschberger; Indira Neeli; Lai Guan Ng; Marko Z. Radic; Konstantinos Ritis; Patrizia Rovere-Querini; Mirco Schapher; Christine Schauer; Hans Uwe Simon; Jeeshan Singh; Panagiotis Skendros; Konstantin Stark; Michael Stürzl; Johan van der Vlag; Peter Vandenabeele; Ljubomir Vitkov; Maren von Köckritz-Blickwede; Cansu Yanginlar; Shida Yousefi; Alexander Zarbock; Georg Schett; Martin Herrmann

doi:10.1038/s41418-021-00805-z

Patients with COVID-19 in the dark-NETs of neutrophils

Maximilian Ackermann, Hans Joachim Anders, Rostyslav Bilyy, Gary L. Bowlin, Christoph Daniel, Rebecca De Lorenzo, Mikala Egeblad, Timo Henneck, Andrés Hidalgo, Markus Hoffmann, Bettina Hohberger, Yogendra Kanthi, Mariana J. Kaplan, Jason S. Knight, Jasmin Knopf, Elzbieta Kolaczkowska, Paul Kubes, Moritz Leppkes, Aparna Mahajan, Angelo A. ManfrediChristian Maueröder, Norma Maugeri, Ioannis Mitroulis, Luis E. Muñoz, Teluguakula Narasaraju, Elisabeth Naschberger, Indira Neeli, Lai Guan Ng, Marko Z. Radic, Konstantinos Ritis, Patrizia Rovere-Querini, Mirco Schapher, Christine Schauer, Hans Uwe Simon, Jeeshan Singh, Panagiotis Skendros, Konstantin Stark, Michael Stürzl, Johan van der Vlag, Peter Vandenabeele, Ljubomir Vitkov, Maren von Köckritz-Blickwede, Cansu Yanginlar, Shida Yousefi, Alexander Zarbock, Georg Schett, Martin Herrmann^*

^*Corresponding author for this work

Clinic of Dermatology, Allergology and Venerology

246 Citations (Scopus)

Abstract

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

Original language	English
Journal	Cell Death and Differentiation
Volume	28
Issue number	11
Pages (from-to)	3125-3139
Number of pages	15
ISSN	1350-9047
DOIs	https://doi.org/10.1038/s41418-021-00805-z
Publication status	Published - 11.2021

Funding

Funding This work was supported by the Swiss National Science Foundation (grant numbers 310030_184816 to H-US and 31003A_173215 to SY); by the CIHR Foundation to PK; by a Rad-boudumc Ph.D. fellowship to CY; by the National Science Center, Poland (NCN) grant no. 2018/29/B/NZ6/00713/ to EK; by the Pershing Square Foundation; by the Singapore Immunology Network (SIgN) core funding, A*STAR, Singapore to LGN; by the Greek General Secretariat for Research and Technology (GSRT), EYDE-ETAK Research & Innovation Programme CYTONET, Grant no: Τ1ΕDK-00617 to PS, IM, and KR; by the Intramural Research Program at NIAMS/NIH to MJK; by the H2020-FETOPEN 861878 NeutroCure to M Herrmann and M Hoffmann; by the Intramural Research Program of the NIH and NHLBI, Lasker Foundation, NIH (K08HL131993, R01HL150392), A. Alfred Taubman Medical Research Institute, Falk Medical Research Trust Catalyst Award, and the JOBST-American Venous Forum Award to YK; Methusalem (BOF16/MET_V/007) to PV; by the grants of the Ministry of Healthcare of Ukraine 0119U101338 and of National Research Foundation of Ukraine 2020.02/0131 to RB; by the grant RTI2018-095497-B-I00 to AH from Ministerio de Ciencia e Innovación (MICINN). the CNIC is supported by MICINN and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MICINN award SEV-2015-0505) to AH; by the Ministerium für Wissenschaft und Kultur, Lower Saxony, Germany (14-76103-184 CORONA-15/ 20) to MvK-B; by the COVID-2020-12371617 grant from the Italian Ministry of Health to AAM, PR-Q, and NM.; by the the intramural support through the CORNET Collaborative Award of 2020 to MR and IN; by the Programm zur Förderung von Corona-Forschung-sprojekten, StMWK, München to M Herrmann, ML, and M Stürzl; by the VW foundation (grant 97744) to M Herrmann, HJA and RB; and the Pershing Square Foundation to ME. We would further like to acknowledge the support of the German Research Foundation (DFG) FOR 2438 subproject 2 to and M Stürzl, SFB/TRR241 subproject A06 to M Stürzl AN372/14-3, and 24-1 to HJA; SCHA 2040/1-1 to CS; project number 387509280 and SFB 1350 to CD; MA 7770/1-1 to CM; SFB 914, SFB1123 and the DZHK to K.S.; TRR241: B04 to ML and M Herrmann; CRC1181: C03 to M Herrmann and M Hoffmann; IZKF and ELAN of FAU to CS; IZKF Münster Za2/001/18, KFO 342, ZA428/18-1, INST 211/984-1 and ZA428/20-1 to AZ, and the EU (ERC-Synergy grant 4D Nanoscope) LM and GS. None of the above-mentioned funders had any role in the paper design, data collection, data analysis, interpretation, or writing of the paper. Open Access funding enabled and organized by Projekt DEAL.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)
Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

2.21-05 Immunology

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

Access to Document

10.1038/s41418-021-00805-z

Cite this

Ackermann, M., Anders, H. J., Bilyy, R., Bowlin, G. L., Daniel, C., De Lorenzo, R., Egeblad, M., Henneck, T., Hidalgo, A., Hoffmann, M., Hohberger, B., Kanthi, Y., Kaplan, M. J., Knight, J. S., Knopf, J., Kolaczkowska, E., Kubes, P., Leppkes, M., Mahajan, A., ... Herrmann, M. (2021). Patients with COVID-19 in the dark-NETs of neutrophils. Cell Death and Differentiation, 28(11), 3125-3139. https://doi.org/10.1038/s41418-021-00805-z

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title = "Patients with COVID-19 in the dark-NETs of neutrophils",

abstract = "SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.",

author = "Maximilian Ackermann and Anders, \{Hans Joachim\} and Rostyslav Bilyy and Bowlin, \{Gary L.\} and Christoph Daniel and \{De Lorenzo\}, Rebecca and Mikala Egeblad and Timo Henneck and Andr{\'e}s Hidalgo and Markus Hoffmann and Bettina Hohberger and Yogendra Kanthi and Kaplan, \{Mariana J.\} and Knight, \{Jason S.\} and Jasmin Knopf and Elzbieta Kolaczkowska and Paul Kubes and Moritz Leppkes and Aparna Mahajan and Manfredi, \{Angelo A.\} and Christian Mauer{\"o}der and Norma Maugeri and Ioannis Mitroulis and Mu{\~n}oz, \{Luis E.\} and Teluguakula Narasaraju and Elisabeth Naschberger and Indira Neeli and Ng, \{Lai Guan\} and Radic, \{Marko Z.\} and Konstantinos Ritis and Patrizia Rovere-Querini and Mirco Schapher and Christine Schauer and Simon, \{Hans Uwe\} and Jeeshan Singh and Panagiotis Skendros and Konstantin Stark and Michael St{\"u}rzl and \{van der Vlag\}, Johan and Peter Vandenabeele and Ljubomir Vitkov and \{von K{\"o}ckritz-Blickwede\}, Maren and Cansu Yanginlar and Shida Yousefi and Alexander Zarbock and Georg Schett and Martin Herrmann",

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year = "2021",

month = nov,

doi = "10.1038/s41418-021-00805-z",

language = "English",

volume = "28",

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Ackermann, M, Anders, HJ, Bilyy, R, Bowlin, GL, Daniel, C, De Lorenzo, R, Egeblad, M, Henneck, T, Hidalgo, A, Hoffmann, M, Hohberger, B, Kanthi, Y, Kaplan, MJ, Knight, JS, Knopf, J, Kolaczkowska, E, Kubes, P, Leppkes, M, Mahajan, A, Manfredi, AA, Maueröder, C, Maugeri, N, Mitroulis, I, Muñoz, LE, Narasaraju, T, Naschberger, E, Neeli, I, Ng, LG, Radic, MZ, Ritis, K, Rovere-Querini, P, Schapher, M, Schauer, C, Simon, HU, Singh, J, Skendros, P, Stark, K, Stürzl, M, van der Vlag, J, Vandenabeele, P, Vitkov, L, von Köckritz-Blickwede, M, Yanginlar, C, Yousefi, S, Zarbock, A, Schett, G & Herrmann, M 2021, 'Patients with COVID-19 in the dark-NETs of neutrophils', Cell Death and Differentiation, vol. 28, no. 11, pp. 3125-3139. https://doi.org/10.1038/s41418-021-00805-z

TY - JOUR

T1 - Patients with COVID-19 in the dark-NETs of neutrophils

AU - Ackermann, Maximilian

AU - Anders, Hans Joachim

AU - Bilyy, Rostyslav

AU - Bowlin, Gary L.

AU - Daniel, Christoph

AU - De Lorenzo, Rebecca

AU - Egeblad, Mikala

AU - Henneck, Timo

AU - Hidalgo, Andrés

AU - Hoffmann, Markus

AU - Hohberger, Bettina

AU - Kanthi, Yogendra

AU - Kaplan, Mariana J.

AU - Knight, Jason S.

AU - Knopf, Jasmin

AU - Kolaczkowska, Elzbieta

AU - Kubes, Paul

AU - Leppkes, Moritz

AU - Mahajan, Aparna

AU - Manfredi, Angelo A.

AU - Maueröder, Christian

AU - Maugeri, Norma

AU - Mitroulis, Ioannis

AU - Muñoz, Luis E.

AU - Narasaraju, Teluguakula

AU - Naschberger, Elisabeth

AU - Neeli, Indira

AU - Ng, Lai Guan

AU - Radic, Marko Z.

AU - Ritis, Konstantinos

AU - Rovere-Querini, Patrizia

AU - Schapher, Mirco

AU - Schauer, Christine

AU - Simon, Hans Uwe

AU - Singh, Jeeshan

AU - Skendros, Panagiotis

AU - Stark, Konstantin

AU - Stürzl, Michael

AU - van der Vlag, Johan

AU - Vandenabeele, Peter

AU - Vitkov, Ljubomir

AU - von Köckritz-Blickwede, Maren

AU - Yanginlar, Cansu

AU - Yousefi, Shida

AU - Zarbock, Alexander

AU - Schett, Georg

AU - Herrmann, Martin

PY - 2021/11

Y1 - 2021/11

N2 - SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

AB - SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

UR - https://www.scopus.com/pages/publications/85106328442

U2 - 10.1038/s41418-021-00805-z

DO - 10.1038/s41418-021-00805-z

M3 - Scientific review articles

C2 - 34031543

AN - SCOPUS:85106328442

SN - 1350-9047

VL - 28

SP - 3125

EP - 3139

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 11

ER -

Patients with COVID-19 in the dark-NETs of neutrophils

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Coronavirus related work

Access to Document

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