C5aR1 Signaling Triggers Lung Immunopathology in COVID-19 Through Neutrophil Extracellular Traps

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.

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References

Kumari P, Rothan H, Natekar J, Stone S, Pathak H, Strate P . Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses. 2021; 13(1). PMC: 7832889. DOI: 10.3390/v13010132. View

van de Veerdonk F, Giamarellos-Bourboulis E, Pickkers P, Derde L, Leavis H, van Crevel R . A guide to immunotherapy for COVID-19. Nat Med. 2022; 28(1):39-50. DOI: 10.1038/s41591-021-01643-9. View

Wauters E, Van Mol P, Garg A, Jansen S, Van Herck Y, Vanderbeke L . Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res. 2021; 31(3):272-290. PMC: 8027624. DOI: 10.1038/s41422-020-00455-9. View

Kooistra E, Van Berkel M, van Kempen N, van Latum C, Bruse N, Frenzel T . Dexamethasone and tocilizumab treatment considerably reduces the value of C-reactive protein and procalcitonin to detect secondary bacterial infections in COVID-19 patients. Crit Care. 2021; 25(1):281. PMC: 8340482. DOI: 10.1186/s13054-021-03717-z. View

Puhl A, Gomes G, Damasceno S, Fritch E, Levi J, Johnson N . Vandetanib Blocks the Cytokine Storm in SARS-CoV-2-Infected Mice. ACS Omega. 2022; 7(36):31935-31944. PMC: 9454268. DOI: 10.1021/acsomega.2c02794. View

Holter J, Pischke S, de Boer E, Lind A, Jenum S, Holten A . Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020; 117(40):25018-25025. PMC: 7547220. DOI: 10.1073/pnas.2010540117. View

Lim E, van Amstel R, de Boer V, van Vught L, de Bruin S, Brouwer M . Complement activation in COVID-19 and targeted therapeutic options: A scoping review. Blood Rev. 2022; 57:100995. PMC: 9338830. DOI: 10.1016/j.blre.2022.100995. View

Garcia C, Weston-Davies W, Russo R, Tavares L, Rachid M, Alves-Filho J . Complement C5 activation during influenza A infection in mice contributes to neutrophil recruitment and lung injury. PLoS One. 2013; 8(5):e64443. PMC: 3655967. DOI: 10.1371/journal.pone.0064443. View

Zuo Y, Yalavarthi S, Shi H, Gockman K, Zuo M, Madison J . Neutrophil extracellular traps in COVID-19. JCI Insight. 2020; 5(11). PMC: 7308057. DOI: 10.1172/jci.insight.138999. View

10.

Duarte-Neto A, Monteiro R, da Silva L, Malheiros D, de Oliveira E, Theodoro-Filho J . Pulmonary and systemic involvement in COVID-19 patients assessed with ultrasound-guided minimally invasive autopsy. Histopathology. 2020; 77(2):186-197. PMC: 7280721. DOI: 10.1111/his.14160. View

11.

Miyabe Y, Miyabe C, Murooka T, Kim E, Newton G, Kim N . Complement C5a Receptor is the Key Initiator of Neutrophil Adhesion Igniting Immune Complex-induced Arthritis. Sci Immunol. 2017; 2(7). PMC: 5436313. DOI: 10.1126/sciimmunol.aaj2195. View

12.

Hoenigl M, Seidel D, Carvalho A, Rudramurthy S, Arastehfar A, Gangneux J . The emergence of COVID-19 associated mucormycosis: a review of cases from 18 countries. Lancet Microbe. 2022; 3(7):e543-e552. PMC: 8789240. DOI: 10.1016/S2666-5247(21)00237-8. View

13.

Gordon A, Mouncey P, Al-Beidh F, Rowan K, Nichol A, Arabi Y . Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021; 384(16):1491-1502. PMC: 7953461. DOI: 10.1056/NEJMoa2100433. View

14.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

15.

Cugno M, Meroni P, Gualtierotti R, Griffini S, Grovetti E, Torri A . Complement activation in patients with COVID-19: A novel therapeutic target. J Allergy Clin Immunol. 2020; 146(1):215-217. PMC: 7224678. DOI: 10.1016/j.jaci.2020.05.006. View

16.

Gerard C, Gerard N . C5A anaphylatoxin and its seven transmembrane-segment receptor. Annu Rev Immunol. 1994; 12:775-808. DOI: 10.1146/annurev.iy.12.040194.004015. View

17.

Niederreiter J, Eck C, Ries T, Hartmann A, Markl B, Buttner-Herold M . Complement Activation the Lectin and Alternative Pathway in Patients With Severe COVID-19. Front Immunol. 2022; 13:835156. PMC: 8884149. DOI: 10.3389/fimmu.2022.835156. View

18.

Woodruff T, Shukla A . The Complement C5a-C5aR1 GPCR Axis in COVID-19 Therapeutics. Trends Immunol. 2020; 41(11):965-967. PMC: 7510552. DOI: 10.1016/j.it.2020.09.008. View

19.

Jiang Y, Zhao G, Song N, Li P, Chen Y, Guo Y . Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect. 2018; 7(1):77. PMC: 5915580. DOI: 10.1038/s41426-018-0063-8. View

20.

Crunfli F, Carregari V, Veras F, Silva L, Nogueira M, Antunes A . Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc Natl Acad Sci U S A. 2022; 119(35):e2200960119. PMC: 9436354. DOI: 10.1073/pnas.2200960119. View