C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps

被引：16

作者：

Silva, Bruna M. ^{[1
,2
]}

Gomes, Giovanni F. ^{[1
]}

Veras, Flavio P. ^{[1
]}

Cambier, Seppe ^{[3
]}

Silva, Gabriel V. L. ^{[1
,2
]}

Quadros, Andreza U. ^{[1
]}

Caetite, Diego B. ^{[1
,2
]}

Nascimento, Daniele C. ^{[1
,2
]}

Silva, Camilla M. ^{[1
,2
]}

Silva, Juliana C. ^{[1
]}

Damasceno, Samara ^{[1
]}

Schneider, Ayda H. ^{[1
]}

Beretta, Fabio ^{[3
]}

Batah, Sabrina S. ^{[4
]}

Castro, Icaro M. S. ^{[5
]}

Paiva, Isadora M. ^{[1
]}

Rodrigues, Tamara ^{[1
,2
]}

Salina, Ana ^{[1
,6
]}

Martins, Ronaldo ^{[6
,7
]}

Cebinelli, Guilherme C. M. ^{[1
,2
]}

Bibo, Naira L. ^{[1
]}

Jorge, Daniel M. ^{[6
,7
]}

Nakaya, Helder I. ^{[5
]}

Zamboni, Dario S. ^{[1
,6
]}

Leiria, Luiz O. ^{[1
,2
]}

Fabro, Alexandre T. ^{[4
]}

Alves-Filho, Jose C. ^{[1
,2
]}

Arruda, Eurico ^{[6
,7
]}

Louzada-Junior, Paulo ^{[1
,8
,9
,10
]}

Oliveira, Rene D. ^{[1
,8
,9
,10
]}

Cunha, Larissa D. ^{[1
,6
]}

Van Mol, Pierre ^{[11
]}

Vanderbeke, Lore ^{[12
]}

Feys, Simon ^{[12
]}

Wauters, Els ^{[11
]}

Brandolini, Laura ^{[13
]}

Aramini, Andrea ^{[13
]}

Cunha, Fernando Q. ^{[1
,2
]}

Koehl, Joerg ^{[14
,15
]}

Allegretti, Marcello ^{[13
]}

Lambrechts, Diether ^{[4
,16
]}

Wauters, Joost ^{[12
,17
]}

Proost, Paul ^{[3
]}

Cunha, Thiago M. ^{[1
,2
]}

机构：

[1] Univ Sao Paulo, Ctr Res Inflammatory Dis CRID, Dept Pharmacol, Ribeirao Preto, SP, Brazil

[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Grad Program Basic & Appl Immunol, Ribeirao Preto, SP, Brazil

[3] Katholieke Univ Leuven, Rega Inst, Dept Microbiol Immunol & Transplantat, Lab Mol Immunol, Leuven, Belgium

[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pathol & Legal Med, Ribeirao Preto, SP, Brazil

[5] Hosp Israelita Albert Einstein, Sao Paulo, Brazil

[6] Univ Sao Paulo, Dept Cell & Mol Biol, Ribeirao Preto, SP, Brazil

[7] Univ Sao Paulo, Virol Res Ctr, Ribeirao Preto, SP, Brazil

[8] Univ Sao Paulo, Div Clin Immunol, Ribeirao Preto, SP, Brazil

[9] Univ Sao Paulo, Div Emergency, Ribeirao Preto, SP, Brazil

[10] Univ Sao Paulo, Infect Dis & Intens Care Unit, Ribeirao Preto Med Sch, Ribeirao Preto, SP, Brazil

[11] Katholieke Univ Leuven, Dept Chron Dis & Metab, Lab Resp Dis & Thorac Surg BREATHE, Leuven, Belgium

[12] Katholieke Univ Leuven, Dept Microbiol Immunol & Transplantat, Lab Clin Infect & Inflammatory Disorders, Leuven, Belgium

[13] Dompe Farmaceut Spa, R&D Dept, Via Campo Pile, Laquila, Italy

[14] Cincinnati Childrens Hosp Med Ctr, Div Immunobiol, Cincinnati, OH USA

[15] Univ Lubeck, Inst Syst Inflammat Res, Ratzebuger Allee, Lubeck, Germany

[16] Katholieke Univ Leuven, VIB, Dept Human Genet, Lab Translat Genet, Leuven, Belgium

[17] Univ Hosp Leuven, Med Intens Care Unit, Leuven, Belgium

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 12期

基金：

巴西圣保罗研究基金会;

关键词：

COMPLEMENT ACTIVATION; INHIBITION; TOCILIZUMAB; INFECTIONS; ROLES; CELLS;

D O I：

10.1172/JCI163105

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that complement component 5a (C5a), through its cellular receptor C5aR1, has potent proinflammatory actions and plays immunopathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway could be involved in COVID-19 pathophysiology. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of critically ill patients with COVID-19 compared with patients with influenza infection, as well as in the lung tissue of K18-hACE2 Tg mice (Tg mice) infected with SARS-CoV-2. Genetic and pharmacological inhibition of C5aR1 signaling ameliorated lung immunopathology in Tg-infected mice. Mechanistically, we found that C5aR1 signaling drives neutrophil extracellular traps-dependent (NETs-dependent) immunopathology. These data confirm the immunopathological role of C5a/C5aR1 signaling in COVID-19 and indicate that antagonists of C5aR1 could be useful for COVID-19 treatment.

引用

页数：18

共 21 条

[1] Vascular occlusion by neutrophil extracellular traps in COVID-19
Leppkes, Moritz
Knopl, Jasmin
Naschberger, Elisabeth
Lindemann, Aylin
Singh, Jeeshan
Herrmann, Irmgard
Stuerzl, Michael
Staats, Leonie
Mahajan, Aparna
Schauer, Christine
Kremer, Anita N.
Voelkl, Simon
Amann, Kerstin
Evert, Katja
Falkies, Christina
Wehrfritz, Andrea
Rieker, Ralf J.
Hartmann, Arndt
Kremer, Andreas E.
Neurath, Markus F.
Munoz, Luis E.
Schett, Georg
Herrmann, Martin
EBIOMEDICINE, 2020, 58
[2] Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19
Tomar, Bhawna
Anders, Hans-Joachim
Desai, Jyaysi
Mulay, Shrikant R.
CELLS, 2020, 9 (06)
[3] COVID-19, neutrophil extracellular traps and vascular complications in obstetric practice
Makatsariya, Alexander
Slukhanchuk, Ekaterina
Bitsadze, Viktoriya
Khizroeva, Jamilya
Tretyakova, Maria
Tsibizova, Valentina
Dobryakov, Andrey
Elalamy, Ismail
Gris, Jean C.
JOURNAL OF PERINATAL MEDICINE, 2020, 48 (09) : 985 - 994
[4] Neutrophil Extracellular Traps (NETs) and Covid-19: A new frontiers for therapeutic modality
Al-Kuraishy, Hayder M.
Al-Gareeb, Ali I.
Al-hussaniy, Hany Akeel
Al-Harcan, Nasser A. Hadi
Alexiou, Athanasios
Batiha, Gaber El-Saber
INTERNATIONAL IMMUNOPHARMACOLOGY, 2022, 104
[5] Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19
Apostolidis, Sokratis A.
Sarkar, Amrita
Giannini, Heather M.
Goel, Rishi R.
Mathew, Divij
Suzuki, Aae
Baxter, Amy E.
Greenplate, Allison R.
Alanio, Cecile
Abdel-Hakeem, Mohamed
Oldridge, Derek A.
Giles, Josephine R.
Wu, Jennifer E.
Chen, Zeyu
Huang, Yinghui Jane
Belman, Jonathan
Pattekar, Ajinkya
Manne, Sasikanth
Kuthuru, Oliva
Dougherty, Jeanette
Weiderhold, Brittany
Weisman, Ariel R.
Ittner, Caroline A. G.
Gouma, Sigrid
Dunbar, Debora
Frank, Ian
Huang, Alexander C.
Vella, Laura A.
Reilly, John P.
Hensley, Scott E.
Rauova, Lubica
Zhao, Liang
Meyer, Nuala J.
Poncz, Mortimer
Abrams, Charles S.
Wherry, E. John
FRONTIERS IN IMMUNOLOGY, 2022, 13
[6] C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19
Aiello, Sistiana
Gastoldi, Sara
Galbusera, Miriam
Ruggenenti, Piero
Portalupi, Valentina
Rota, Stefano
Rubis, Nadia
Liguori, Lucia
Conti, Sara
Tironi, Matteo
Gamba, Sara
Santarsiero, Donata
Benigni, Ariela
Remuzzi, Giuseppe
Noris, Marina
BLOOD ADVANCES, 2022, 6 (03) : 866 - 881
[7] Mechanism of activation and biased signaling in complement receptor C5aR1
Feng, Yuying
Zhao, Chang
Deng, Yue
Wang, Heli
Ma, Liang
Liu, Sicen
Tian, Xiaowen
Wang, Bo
Bin, Yan
Chen, Peipei
Yan, Wei
Fu, Ping
Shao, Zhenhua
CELL RESEARCH, 2023, 33 (04) : 312 - 324
[8] Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis
Carvelli, Julien
Demaria, Olivier
Vely, Frederic
Batista, Luciana
Benmansour, Nassima Chouaki
Fares, Joanna
Carpentier, Sabrina
Thibult, Marie-Laure
Morel, Ariane
Remark, Romain
Andre, Pascale
Represa, Agnes
Piperoglou, Christelle
Cordier, Pierre Yves
Le Dault, Erwan
Guervilly, Christophe
Simeone, Pierre
Gainnier, Marc
Morel, Yannis
Ebbo, Mikael
Schleinitz, Nicolas
Vivier, Eric
NATURE, 2020, 588 (7836) : 146 - +
[9] Transcriptional Insights of Oxidative Stress and Extracellular Traps in Lung Tissues of Fatal COVID-19 Cases
Hosseini, Aref
Stojkov, Darko
Fettrelet, Timothee
Bilyy, Rostyslav
Yousefi, Shida
Simon, Hans-Uwe
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (03)
[10] Insights into the Role of Neutrophils and Neutrophil Extracellular Traps in Causing Cardiovascular Complications in Patients with COVID-19: A Systematic Review
Nappi, Francesco
Bellomo, Francesca
Singh, Sanjeet Singh Avtaar
JOURNAL OF CLINICAL MEDICINE, 2022, 11 (09)

← 1 2 3 →