Skip to main content

Advertisement

SpringerLink
Log in

Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

This study includes no data deposited in external repositories. Data are available from the corresponding author on request.

References

  1. Hughes CE, Nibbs RJB (2018) A guide to chemokines and their receptors. FEBS J 285(16):2944–2971. https://doi.org/10.1111/febs.14466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Janssens R, Struyf S, Proost P (2018) The unique structural and functional features of CXCL12. Cell Mol Immunol 15(4):299–311. https://doi.org/10.1038/cmi.2017.107

    Article  CAS  PubMed  Google Scholar 

  3. Gutjahr JC, Crawford KS, Jensen DR, Naik P, Peterson FC, Samson GPB et al (2021) The dimeric form of CXCL12 binds to atypical chemokine receptor 1. Sci Signal 14(696):eabc9012. https://doi.org/10.1126/scisignal.abc9012

  4. Yen YC, Schafer CT, Gustavsson M, Eberle SA, Dominik PK, Deneka D et al (2022) Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias. Sci Adv 8(28):eabn8063. https://doi.org/10.1126/sciadv.abn8063

  5. Busillo JM, Benovic JL (2007) Regulation of CXCR4 signaling. Biochim Biophys Acta 1768(4):952–963. https://doi.org/10.1016/j.bbamem.2006.11.002

    Article  CAS  PubMed  Google Scholar 

  6. Wang M, Lin T, Wang Y, Gao S, Yang Z, Hong X et al (2017) CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells. Onco Targets Ther 10:3215–3224. https://doi.org/10.2147/OTT.S133055

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sun Y, Cheng Z, Ma L, Pei G (2002) Beta-arrestin2 is critically involved in CXCR4-mediated chemotaxis, and this is mediated by its enhancement of p38 MAPK activation. J Biol Chem 277(51):49212–49219. https://doi.org/10.1074/jbc.M207294200

    Article  CAS  PubMed  Google Scholar 

  8. Lau S, Feitzinger A, Venkiteswaran G, Wang J, Lewellis SW, Koplinski CA et al (2020) A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration. Nat Cell Biol 22(3):266–273. https://doi.org/10.1038/s41556-020-0465-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kunz L, Schroeder T (2019) A 3D tissue-wide digital imaging pipeline for quantitation of secreted molecules shows absence of CXCL12 gradients in bone marrow. Cell Stem Cell 25(6):846–54.e4. https://doi.org/10.1016/j.stem.2019.10.003

    Article  CAS  PubMed  Google Scholar 

  10. Eash KJ, Greenbaum AM, Gopalan PK, Link DC (2010) CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow. J Clin Invest 120(7):2423–2431. https://doi.org/10.1172/JCI41649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Janssens R, Struyf S, Proost P (2018) Pathological roles of the homeostatic chemokine CXCL12. Cytokine Growth Factor Rev 44:51–68. https://doi.org/10.1016/j.cytogfr.2018.10.004

    Article  CAS  PubMed  Google Scholar 

  12. Cambier S, Gouwy M, Proost P (2023) The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention. Cell Mol Immunol 20(3):217–251. https://doi.org/10.1038/s41423-023-00974-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lim K, Hyun YM, Lambert-Emo K, Capece T, Bae S, Miller R et al (2015) Neutrophil trails guide influenza-specific CD8+ T cells in the airways. Science 349(6252):aaa4352. https://doi.org/10.1126/science.aaa4352

  14. Yamada M, Kubo H, Kobayashi S, Ishizawa K, He M, Suzuki T et al (2011) The increase in surface CXCR4 expression on lung extravascular neutrophils and its effects on neutrophils during endotoxin-induced lung injury. Cell Mol Immunol 8(4):305–314. https://doi.org/10.1038/cmi.2011.8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hoshino M, Aoike N, Takahashi M, Nakamura Y, Nakagawa T (2003) Increased immunoreactivity of stromal cell-derived factor-1 and angiogenesis in asthma. Eur Respir J 21(5):804–809. https://doi.org/10.1183/09031936.03.00082002

    Article  CAS  PubMed  Google Scholar 

  16. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10(8):858–864. https://doi.org/10.1038/nm1075

    Article  CAS  PubMed  Google Scholar 

  17. McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP et al (2017) Hypoxia-inducible factor 1α signaling promotes repair of the alveolar epithelium after acute lung injury. Am J Pathol 187(8):1772–1786. https://doi.org/10.1016/j.ajpath.2017.04.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ghosh MC, Makena PS, Gorantla V, Sinclair SE, Waters CM (2012) CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol 302(9):L846–L856. https://doi.org/10.1152/ajplung.00321.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vanheule V, Metzemaekers M, Janssens R, Struyf S, Proost P (2018) How post-translational modifications influence the biological activity of chemokines. Cytokine 109:29–51. https://doi.org/10.1016/j.cyto.2018.02.026

    Article  CAS  PubMed  Google Scholar 

  20. Janssens R, Mortier A, Boff D, Ruytinx P, Gouwy M, Vantilt B et al (2017) Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes. Biochem Pharmacol 132:92–101. https://doi.org/10.1016/j.bcp.2017.03.009

    Article  CAS  PubMed  Google Scholar 

  21. Valenzuela-Fernández A, Planchenault T, Baleux F, Staropoli I, Le-Barillec K, Leduc D et al (2002) Leukocyte elastase negatively regulates Stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem 277(18):15677–15689. https://doi.org/10.1074/jbc.M111388200

    Article  CAS  PubMed  Google Scholar 

  22. Delgado MB, Clark-Lewis I, Loetscher P, Langen H, Thelen M, Baggiolini M et al (2001) Rapid inactivation of stromal cell-derived factor-1 by cathepsin G associated with lymphocytes. Eur J Immunol 31(3):699–707. https://doi.org/10.1002/1521-4141(200103)31:3%3c699::aid-immu699%3e3.0.co;2-6

    Article  CAS  PubMed  Google Scholar 

  23. McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I et al (2001) Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276(47):43503–43508. https://doi.org/10.1074/jbc.M107736200

    Article  CAS  PubMed  Google Scholar 

  24. Marquez-Curtis L, Jalili A, Deiteren K, Shirvaikar N, Lambeir AM, Janowska-Wieczorek A (2008) Carboxypeptidase M expressed by human bone marrow cells cleaves the C-terminal lysine of stromal cell-derived factor-1alpha: another player in hematopoietic stem/progenitor cell mobilization? Stem Cells 26(5):1211–1220. https://doi.org/10.1634/stemcells.2007-0725

    Article  CAS  PubMed  Google Scholar 

  25. Davis DA, Singer KE, De La Luz SM, Narazaki M, Yang F, Fales HM et al (2005) Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1alpha in the circulation. Blood 105(12):4561–4568. https://doi.org/10.1182/blood-2004-12-4618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Metzemaekers M, Abouelasrar Salama S, Vandooren J, Mortier A, Janssens R, Vandendriessche S et al (2021) From ELISA to immunosorbent tandem mass spectrometry proteoform analysis: the example of CXCL8/Interleukin-8. Front Immunol 12:644725. https://doi.org/10.3389/fimmu.2021.644725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Merad M, Blish CA, Sallusto F, Iwasaki A (2022) The immunology and immunopathology of COVID-19. Science 375(6585):1122–1127. https://doi.org/10.1126/science.abm8108

    Article  CAS  PubMed  Google Scholar 

  28. Wong LR, Perlman S (2022) Immune dysregulation and immunopathology induced by SARS-CoV-2 and related coronaviruses - are we our own worst enemy? Nat Rev Immunol 22(1):47–56. https://doi.org/10.1038/s41577-021-00656-2

    Article  CAS  PubMed  Google Scholar 

  29. Vanderbeke L, Van Mol P, Van Herck Y, De Smet F, Humblet-Baron S, Martinod K et al (2021) Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity. Nat Commun 12(1):4117. https://doi.org/10.1038/s41467-021-24360-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Metzemaekers M, Cambier S, Blanter M, Vandooren J, de Carvalho AC, Malengier-Devlies B et al (2021) Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019. Clin Transl Immunol 10(4):e1271. https://doi.org/10.1002/cti2.1271

    Article  CAS  Google Scholar 

  31. Ghanem M, Homps-Legrand M, Garnier M, Morer L, Goletto T, Frija-Masson J et al (2021) Blood fibrocytes are associated with severity and prognosis in COVID-19 pneumonia. Am J Physiol Lung Cell Mol Physiol 321(5):L847–L858. https://doi.org/10.1152/ajplung.00105.2021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martínez-Fleta P, Vera-Tomé P, Jiménez-Fernández M, Requena S, Roy-Vallejo E, Sanz-García A et al (2021) A differential signature of circulating miRNAs and cytokines between COVID-19 and community-acquired pneumonia uncovers novel physiopathological mechanisms of COVID-19. Front Immunol 12:815651. https://doi.org/10.3389/fimmu.2021.815651

    Article  CAS  PubMed  Google Scholar 

  33. Cambier S, Metzemaekers M, de Carvalho AC, Nooyens A, Jacobs C, Vanderbeke L et al (2022) Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza. JCI Insight 7(1):e155055. https://doi.org/10.1172/jci.insight.155055

    Article  PubMed  PubMed Central  Google Scholar 

  34. Leng L, Cao R, Ma J, Mou D, Zhu Y, Li W et al (2020) Pathological features of COVID-19-associated lung injury: a preliminary proteomics report based on clinical samples. Signal Transduct Target Ther 5(1):240. https://doi.org/10.1038/s41392-020-00355-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zaid Y, Doré É, Dubuc I, Archambault AS, Flamand O, Laviolette M et al (2021) Chemokines and eicosanoids fuel the hyperinflammation within the lungs of patients with severe COVID-19. J Allergy Clin Immunol 148(2):368–80.e3. https://doi.org/10.1016/j.jaci.2021.05.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Petty JM, Sueblinvong V, Lenox CC, Jones CC, Cosgrove GP, Cool CD et al (2007) Pulmonary stromal-derived factor-1 expression and effect on neutrophil recruitment during acute lung injury. J Immunol 178(12):8148–8157. https://doi.org/10.4049/jimmunol.178.12.8148

    Article  CAS  PubMed  Google Scholar 

  37. Noto A, Joo V, Mancarella A, Suffiotti M, Pellaton C, Fenwick C et al (2022) CXCL12 and CXCL13 cytokine serum levels are associated with the magnitude and the quality of SARS-CoV-2 humoral responses. Viruses 14(12):2665. https://doi.org/10.3390/v14122665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Alturaiki W, Alkadi H, Alamri S, Awadalla ME, Alfaez A, Mubarak A et al (2023) Association between the expression of toll-like receptors, cytokines, and homeostatic chemokines in SARS-CoV-2 infection and COVID-19 severity. Heliyon 9(1):e12653. https://doi.org/10.1016/j.heliyon.2022.e12653

    Article  CAS  PubMed  Google Scholar 

  39. Xu ZS, Shu T, Kang L, Wu D, Zhou X, Liao BW et al (2020) Temporal profiling of plasma cytokines, chemokines and growth factors from mild, severe and fatal COVID-19 patients. Signal Transduct Target Ther 5(1):100. https://doi.org/10.1038/s41392-020-0211-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ackermann M, Mentzer SJ, Kolb M, Jonigk D (2020) Inflammation and intussusceptive angiogenesis in COVID-19: everything in and out of flow. Eur Respir J 56(5):2003147. https://doi.org/10.1183/13993003.03147-2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dimova I, Karthik S, Makanya A, Hlushchuk R, Semela D, Volarevic V et al (2019) SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception. J Cell Mol Med 23(6):3916–3926. https://doi.org/10.1111/jcmm.14269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Silvin A, Chapuis N, Dunsmore G, Goubet AG, Dubuisson A, Derosa L et al (2020) Elevated calprotectin and abnormal myeloid cell subsets discriminate severe from mild COVID-19. Cell 182(6):1401–1418.e18. https://doi.org/10.1016/j.cell.2020.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wauters E, Van Mol P, Garg AD, Jansen S, Van Herck Y, Vanderbeke L et al (2021) Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res 31(3):272–290. https://doi.org/10.1038/s41422-020-00455-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peng Y, Wu Q, Tang H, Chen J, Wu Q, Yuan X et al (2020) NLRP3 regulated CXCL12 expression in acute neutrophilic lung injury. J Inflamm Res 13:377–386. https://doi.org/10.2147/JIR.S259633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bénard A, Jacobsen A, Brunner M, Krautz C, Klösch B, Swierzy I et al (2021) Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections. Nat Commun 12(1):1112. https://doi.org/10.1038/s41467-021-21310-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Verleden SE, Ruttens D, Vos R, Vandermeulen E, Moelants E, Mortier A et al (2015) Differential cytokine, chemokine and growth factor expression in phenotypes of chronic lung allograft dysfunction. Transplantation 99(1):86–93. https://doi.org/10.1097/TP.0000000000000269

    Article  CAS  PubMed  Google Scholar 

  47. Metzemaekers M, Van Damme J, Mortier A, Proost P (2016) Regulation of chemokine activity - a focus on the role of dipeptidyl peptidase IV/CD26. Front Immunol 7:483. https://doi.org/10.3389/fimmu.2016.00483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shen W, Weng Z, Fan M, Wang S, Wang R, Zhang Y et al (2020) Mechanisms by which the MBD2/miR-301a-5p/CXCL12/CXCR4 pathway regulates acute exacerbations of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 15:2561–2572. https://doi.org/10.2147/COPD.S261522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sivakumar P, Ammar R, Thompson JR, Luo Y, Streltsov D, Porteous M et al (2021) Integrated plasma proteomics and lung transcriptomics reveal novel biomarkers in idiopathic pulmonary fibrosis. Respir Res 22(1):273. https://doi.org/10.1186/s12931-021-01860-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Proost P, Struyf S, Schols D, Durinx C, Wuyts A, Lenaerts JP et al (1998) Processing by CD26/dipeptidyl-peptidase IV reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett 432(1–2):73–76. https://doi.org/10.1016/s0014-5793(98)00830-8

    Article  CAS  PubMed  Google Scholar 

  51. De La Luz SM, Yang F, Narazaki M, Salvucci O, Davis D, Yarchoan R et al (2004) Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood 103(7):2452–2459. https://doi.org/10.1182/blood-2003-08-2857

    Article  CAS  Google Scholar 

  52. Christopherson KW, Hangoc G, Broxmeyer HE (2002) Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 169(12):7000–7008. https://doi.org/10.4049/jimmunol.169.12.7000

    Article  CAS  PubMed  Google Scholar 

  53. Richter R, Jochheim-Richter A, Ciuculescu F, Kollar K, Seifried E, Forssmann U et al (2014) Identification and characterization of circulating variants of CXCL12 from human plasma: effects on chemotaxis and mobilization of hematopoietic stem and progenitor cells. Stem Cells Dev 23(16):1959–1974. https://doi.org/10.1089/scd.2013.0524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang W, Choi BK, Li W, Lao Z, Lee AY, Souza SC et al (2014) Quantification of intact and truncated stromal cell-derived factor-1α in circulation by immunoaffinity enrichment and tandem mass spectrometry. J Am Soc Mass Spectrom 25(4):614–625. https://doi.org/10.1007/s13361-013-0822-7

    Article  CAS  PubMed  Google Scholar 

  55. Todeschini M, Macconi D, Fernández NG, Ghilardi M, Anabaya A, Binda E et al (2002) Effect of acetate-free biofiltration and bicarbonate hemodialysis on neutrophil activation. Am J Kidney Dis 40(4):783–793. https://doi.org/10.1053/ajkd.2002.35690

    Article  CAS  PubMed  Google Scholar 

  56. Al-Kuraishy HM, Al-Gareeb AI, Qusty N, Alexiou A, Batiha GE (2022) Impact of Sitagliptin on Non-diabetic Covid-19 Patients. Curr Mol Pharmacol 15(4):683–692. https://doi.org/10.2174/1874467214666210902115650

    Article  CAS  PubMed  Google Scholar 

  57. Aikawa N, Kawasaki Y (2014) Clinical utility of the neutrophil elastase inhibitor sivelestat for the treatment of acute respiratory distress syndrome. Ther Clin Risk Manag 10:621–629. https://doi.org/10.2147/TCRM.S65066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. McElvaney OJ, McEvoy NL, Boland F, McElvaney OF, Hogan G, Donnelly K et al (2022) A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19. Med (N Y) 3(4):233–248.e6. https://doi.org/10.1016/j.medj.2022.03.001

    Article  CAS  Google Scholar 

  59. Seren S, Derian L, Keleş I, Guillon A, Lesner A, Gonzalez L et al (2021) Proteinase release from activated neutrophils in mechanically ventilated patients with non-COVID-19 and COVID-19 pneumonia. Eur Respir J 57(4):2003755 https://doi.org/10.1183/13993003.03755-2020

    Article  CAS  PubMed Central  Google Scholar 

  60. Houghton AM (2015) Matrix metalloproteinases in destructive lung disease. Matrix Biol 44–46:167–174. https://doi.org/10.1016/j.matbio.2015.02.002

    Article  CAS  PubMed  Google Scholar 

  61. Vågesjö E, Öhnstedt E, Mortier A, Lofton H, Huss F, Proost P et al (2018) Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria. Proc Natl Acad Sci U S A 115(8):1895–1900. https://doi.org/10.1073/pnas.1716580115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Öhnstedt E, Lofton Tomenius H, Frank P, Roos S, Vågesjö E, Phillipson M (2022) Accelerated wound healing in minipigs by on-site production and delivery of CXCL12 by transformed lactic acid bacteria. Pharmaceutics 14(2):229. https://doi.org/10.3390/pharmaceutics14020229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Janssens R, Mortier A, Boff D, Vanheule V, Gouwy M, Franck C et al (2016) Natural nitration of CXCL12 reduces its signaling capacity and chemotactic activity in vitro and abrogates intra-articular lymphocyte recruitment in vivo. Oncotarget 7(38):62439–62459. https://doi.org/10.18632/oncotarget.11516

    Article  PubMed  PubMed Central  Google Scholar 

  64. Janssens R, Boff D, Ruytinx P, Mortier A, Vanheule V, Larsen O et al (2018) Peroxynitrite exposure of CXCL12 impairs monocyte, lymphocyte and endothelial cell chemotaxis, lymphocyte extravasation in vivo and anti-HIV-1 activity. Front Immunol 9:1933. https://doi.org/10.3389/fimmu.2018.01933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Struyf S, Noppen S, Loos T, Mortier A, Gouwy M, Verbeke H et al (2009) Citrullination of CXCL12 differentially reduces CXCR4 and CXCR7 binding with loss of inflammatory and anti-HIV-1 activity via CXCR4. J Immunol 182(1):666–674. https://doi.org/10.4049/jimmunol.182.1.666

    Article  CAS  PubMed  Google Scholar 

  66. Yu K, Proost P (2022) Insights into peptidylarginine deiminase expression and citrullination pathways. Trends Cell Biol 32(9):746–761. https://doi.org/10.1016/j.tcb.2022.01.014

    Article  CAS  PubMed  Google Scholar 

  67. Sadir R, Imberty A, Baleux F, Lortat-Jacob H (2004) Heparan sulfate/heparin oligosaccharides protect stromal cell-derived factor-1 (SDF-1)/CXCL12 against proteolysis induced by CD26/dipeptidyl peptidase IV. J Biol Chem 279(42):43854–43860. https://doi.org/10.1074/jbc.M405392200

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Figure 7 and Figure S1 were created with BioRender.com.

Funding

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).

Author information

Author notes

  1. Seppe Cambier and Fabio Beretta have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Rega - Herestraat 49, Box 1042, 3000, Leuven, Belgium

    Seppe Cambier, Fabio Beretta, Noëmie Pörtner, Mieke Metzemaekers, Ana Carolina de Carvalho, Mieke Gouwy & Paul Proost

  2. Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil

    Ana Carolina de Carvalho & Rafael Elias Marques

  3. Department of Genetics, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

    Ana Carolina de Carvalho

  4. Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium

    Erik Martens

  5. Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium

    Janne Kaes, Celine Aelbrecht, Els Wauters, Bart Vanaudenaerde & Robin Vos

  6. Medical Intensive Care Unit, Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium

    Cato Jacobs, Philippe Meersseman, Greet Hermans & Joost Wauters

  7. Laboratory of Translational Genetics, Department of Human Genetics, VIB-KU Leuven, Leuven, Belgium

    Pierre Van Mol

  8. Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium

    Els Wauters & Robin Vos

  9. Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium

    Greet Hermans

  10. Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium

    Joost Wauters

Authors
  1. Seppe Cambier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fabio Beretta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noëmie Pörtner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mieke Metzemaekers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Carolina de Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Erik Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Janne Kaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Celine Aelbrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cato Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pierre Van Mol
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Els Wauters
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Philippe Meersseman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Greet Hermans
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rafael Elias Marques
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Bart Vanaudenaerde
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Robin Vos
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Joost Wauters
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Mieke Gouwy
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Paul Proost
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SC, FB, MG, and PP designed the experiments. SC, FB, NP, MM, ACDC, and EM performed the experiments and analyzed the data. JK, CA, CJ, PVM, EW, PM, GH, BV, RV, and JW were involved in collection of patient samples and clinical data analysis. REM provided resources. SC and FB visualized the data. JW, MG, and PP supervised this study. SC and FB wrote the original draft of this manuscript. All the authors reviewed, edited, and approved the final version of the manuscript.

Corresponding author

Correspondence to Paul Proost.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The Ethics Committee of the University Hospital Leuven approved this study (S63881, S51577, S61168, S58418, S63357).

Consent to participate

Written informed consent was obtained from all study participants or their legal representatives according to the ethical guidelines of the Declaration of Helsinki.

Consent to publish

This manuscript contains no individual person’s data.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1059 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cambier, S., Beretta, F., Pörtner, N. et al. Proteolytic inactivation of CXCL12 in the lungs and circulation of COVID-19 patients. Cell. Mol. Life Sci. 80, 234 (2023). https://doi.org/10.1007/s00018-023-04870-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-023-04870-0

Keywords

Search

Navigation