Goldblatt, J;
Lawrenson, RA;
Muir, L;
Dattani, S;
Hoffland, A;
Tsuchiya, T;
Kanegasaki, S;
... Pease, JE; + view all
(2019)
A Requirement for Neutrophil Glycosaminoglycans in Chemokine:Receptor Interactions Is Revealed by the Streptococcal Protease SpyCEP.
The Journal of Immunology
, 202
(11)
pp. 3246-3255.
10.4049/jimmunol.1801688.
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Abstract
To evade the immune system, the lethal human pathogen Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminal α-helix of CXCL8, resulting in markedly impaired recruitment of neutrophils to sites of invasive infection. The basis for chemokine inactivation by SpyCEP is, however, poorly understood, as the core domain of CXCL8 known to interact with CXCL8 receptors is unaffected by enzymatic cleavage. We examined the in vitro migration of human neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. SpyCEP-mediated cleavage of CXCL8 also impaired CXCL8-induced migration of transfectants expressing the human chemokine receptors CXCR1 or CXCR2. Despite possessing an intact N terminus and preserved disulfide bonds, SpyCEP-cleaved CXCL8 had impaired binding to both CXCR1 and CXCR2, pointing to a requirement for the C-terminal α-helix. SpyCEP-cleaved CXCL8 had similarly impaired binding to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans was observed to ablate neutrophil navigation of a CXCL8 gradient, whereas navigation of an fMLF gradient remained largely intact. We conclude, therefore, that SpyCEP cleavage of CXCL8 results in chemokine inactivation because of a requirement for glycosaminoglycan binding in productive chemokine:receptor interactions. This may inform strategies to inhibit the activity of SpyCEP, but may also influence future approaches to inhibit unwanted chemokine-induced inflammation.
| Type: | Article |
|---|---|
| Title: | A Requirement for Neutrophil Glycosaminoglycans in Chemokine:Receptor Interactions Is Revealed by the Streptococcal Protease SpyCEP |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.4049/jimmunol.1801688 |
| Publisher version: | https://doi.org/10.4049/jimmunol.1801688 |
| Language: | English |
| Additional information: | © 2019 The Authors This article is distributed under the terms of the CC BY 4.0 Unported license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Animals, Cells, Cultured, Glycosaminoglycans, Heparin, Humans, Interleukin-8, Mice, Neutrophils, Peptide Hydrolases, Protein Binding, Protein Engineering, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Streptococcal Infections, Streptococcus pyogenes |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10094206 |
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