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Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients.
Cambier, Seppe; Beretta, Fabio; Pörtner, Noëmie; Metzemaekers, Mieke; de Carvalho, Ana Carolina; Martens, Erik; Kaes, Janne; Aelbrecht, Celine; Jacobs, Cato; Van Mol, Pierre; Wauters, Els; Meersseman, Philippe; Hermans, Greet; Marques, Rafael Elias; Vanaudenaerde, Bart; Vos, Robin; Wauters, Joost; Gouwy, Mieke; Proost, Paul.
Afiliação
  • Cambier S; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium.
  • Beretta F; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium.
  • Pörtner N; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium.
  • Metzemaekers M; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium.
  • de Carvalho AC; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium.
  • Martens E; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.
  • Kaes J; Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil.
  • Aelbrecht C; Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium.
  • Jacobs C; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
  • Van Mol P; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
  • Wauters E; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Meersseman P; Laboratory of Translational Genetics, Department of Human Genetics, VIB-KU Leuven, Leuven, Belgium.
  • Hermans G; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
  • Marques RE; Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.
  • Vanaudenaerde B; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Vos R; Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
  • Wauters J; Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
  • Gouwy M; Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil.
  • Proost P; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Cell Mol Life Sci ; 80(8): 234, 2023 Jul 28.
Article em En | MEDLINE | ID: mdl-37505242
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: COVID-19 Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: COVID-19 Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article