Neutrophil glycosaminoglycan: diversity and functions – NEUTROGAG

Neutrophils play a central role in the human immune response against pathogenic bacteria but also in the regulation of the overall immune response. In the NEUTROGAG project, we propose to characterize a new family of molecules, the glycosaminoglycans or GAGs. The presence of GAGs in neutrophils is shown during the 50-60’s, using old techniques and have not been further characterized since then. The proposed project is based on original observations made by Partner 1, who has identified that neutrophil secrete a GAG-containing polymeric compound with antimicrobial activities, which has been named proteoglycofili or PGF (André et al, 2022, BioRxiv). In this original study, Partners 1&2 identified two GAGs composing PGF: hyaluronic acid and chondroitin sulfate. They have shown that these GAGs are essential for PGF fibrillar organization and antimicrobial activity (degradation of bacterial virulence factors and inhibition of bacteria growth). They even identified that Neutrophil Extracellular Traps are contend GAGs. This original observation will be of a great interest for a wide community of immunologists.
In the NEUTROGAG project, experts in microbiology, immunology, glycobiology and cell biology will join their efforts to define the complete repertoire of GAGs in PGF and NETs. The localization and function of GAGs in neutrophil nucleus architecture and cell shape will be investigated under basal conditions and upon activation. GAGs have been shown to interact with a high affinity with chemokines: this property will be defined regarding neutrophil GAGs in order to better appreciate their contribution to the formation of chemokine concentration gradients, mediating the recruitment of neutrophils to infectious or inflammatory sites. In the last part of the project, the impact of intracellular GAGs on the control of neutrophil dynamics will be investigated using microfluidic approaches combined to live microscopy.
Results obtained during the NEUTROGAG project will help to better understand the importance of GAGs in the physiology of neutrophils and their contribution to their antimicrobial functions. The identification of GAG-degrading enzymes may open new doors for the development of new therapeutics to treat inflammatory diseases.