Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul...
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul Proost
ARTIGO
Inglês
Agradecimentos: Figure 7 and Figure S1 were created with BioRender.com. This work was supported by research grants from Katholieke Universiteit Leuven (KU Leuven; C1 grant C16/17/010) and Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen; grant G0F8822N). This work was also supported by a...
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Agradecimentos: Figure 7 and Figure S1 were created with BioRender.com. This work was supported by research grants from Katholieke Universiteit Leuven (KU Leuven; C1 grant C16/17/010) and Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen; grant G0F8822N). This work was also supported by a KU Leuven (CONTAGIOUS) and a University Hospitals Leuven (UZ Leuven; KOOR project) internal grant. SC received a PhD fellowship from FWO-Vlaanderen (grant number 11A4220N). ACDC is supported by a Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) PhD fellowship. REM is a Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Research Fellow and supported by a FWO-Vlaanderen FAPESP bilateral agreement research grant (2021/05519-0)
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Abstract: The human chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is involved in several homeostatic processes and pathologies through interaction with its cognate G protein-coupled receptor CXCR4. Recent research has shown that CXCL12 is present in the lungs and circulation of patients...
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Abstract: The human chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is involved in several homeostatic processes and pathologies through interaction with its cognate G protein-coupled receptor CXCR4. Recent research has shown that CXCL12 is present in the lungs and circulation of patients with coronavirus disease 2019 (COVID-19). However, the question whether the detected CXCL12 is bioactive was not addressed. Indeed, the activity of CXCL12 is regulated by NH2- and COOH-terminal post-translational proteolysis, which significantly impairs its biological activity. The aim of the present study was to characterize proteolytic processing of CXCL12 in broncho-alveolar lavage (BAL) fluid and blood plasma samples from critically ill COVID-19 patients. Therefore, we optimized immunosorbent tandem mass spectrometry proteoform analysis (ISTAMPA) for detection of CXCL12 proteoforms. In patient samples, this approach uncovered that CXCL12 is rapidly processed by site-specific NH2- and COOH-terminal proteolysis and ultimately degraded. This proteolytic inactivation occurred more rapidly in COVID-19 plasma than in COVID-19 BAL fluids, whereas BAL fluid samples from stable lung transplantation patients and the non-affected lung of lung cancer patients (control groups) hardly induced any processing of CXCL12. In COVID-19 BAL fluids with high proteolytic activity, processing occurred exclusively NH2-terminally and was predominantly mediated by neutrophil elastase. In low proteolytic activity BAL fluid and plasma samples, NH2- and COOH-terminal proteolysis by CD26 and carboxypeptidases were observed. Finally, protease inhibitors already approved for clinical use such as sitagliptin and sivelestat prevented CXCL12 processing and may therefore be of pharmacological interest to prolong CXCL12 half-life and biological activity in vivo
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FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP
2021/05519-0
CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ
Fechado
Cambie, Seppe
Autor
Beretta, Fabio
Autor
Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul...
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul Proost
Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul...
Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Erik Martens, Janne Kaes, Celine Aelbrecht, Cato Jacobs, Pierre van Mol, Els Wauters, Philippe Meersseman, Greet Hermans, Rafael Elias Marques, Bart Vanaudenaerde, Robin Vos, Joost Wauters, Mieke Gouwy, Paul Proost
Fontes
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Cellular and molecular life sciences v. 80, n. art. 234, July 2023 |