DOI: 10.1101/461418Nov 4, 2018Paper

A requirement for neutrophil glycosaminoglycans in the navigation of chemokine gradients is revealed by the streptococcal protease SpyCEP

BioRxiv : the Preprint Server for Biology
Jenny GoldblattJames Edward Pease

Abstract

Neutrophils provide a first line of defense against bacteria and are guided to infected tissues by chemoattractants, notably the chemokine CXCL8. To evade the immune system, the bacterium Streptococcus pyogenes produces SpyCEP, an enzyme that cleaves the C-terminus of CXCL8, rendering it impotent. The basis for chemokine inactivation by SpyCEP is poorly understood. We examined the in vitro migration of neutrophils and observed that their ability to efficiently navigate a CXCL8 gradient was compromised following CXCL8 cleavage by SpyCEP. Despite possessing an intact N-terminus, SpyCEP-cleaved CXCL8 had impaired binding not only to the chemokine receptors CXCR1 and CXCR2 but also to the glycosaminoglycan heparin. Enzymatic removal of neutrophil glycosaminoglycans similarly impaired navigation of a CXCL8 gradient, but not an fMLP gradient. We conclude that during cell migration, neutrophil glycosaminoglycans sample environmental chemokines, promoting interactions with chemokine receptors, a process that is necessary for productive chemokine:receptor interactions. This may inform strategies to inhibit SpyCEP, thereby promoting bacterial clearance by the host immune system.

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