RGD Reference Report - Glycosaminoglycans are important mediators of neutrophilic inflammation in vivo. - Rat Genome Database

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Glycosaminoglycans are important mediators of neutrophilic inflammation in vivo.

Authors: Gschwandtner, Martha  Strutzmann, Elisabeth  Teixeira, Mauro M  Anders, Hans J  Diedrichs-Möhring, Maria  Gerlza, Tanja  Wildner, Gerhild  Russo, Remo C  Adage, Tiziana  Kungl, Andreas J 
Citation: Gschwandtner M, etal., Cytokine. 2017 Mar;91:65-73. doi: 10.1016/j.cyto.2016.12.008. Epub 2016 Dec 21.
RGD ID: 150520199
Pubmed: PMID:28011398   (View Abstract at PubMed)
DOI: DOI:10.1016/j.cyto.2016.12.008   (Journal Full-text)

The pro-inflammatory chemokine interleukin-8 (CXCL8) exerts its function by establishing a chemotactic gradient in infected or damaged tissues to guide neutrophil granulocytes to the site of inflammation via its G protein-coupled receptors (GPCRs) CXCR1 and CXCR2 located on neutrophils. Endothelial glycosaminoglycans (GAGs) have been proposed to support the chemotactic gradient formation and thus the inflammatory response by presenting the chemokine to approaching leukocytes. In this study, we show that neutrophil transmigration in vitro can be reduced by adding soluble GAGs and that this process is specific with respect to the nature of the glycan. To further investigate the GAG influence on neutrophil migration, we have used an engineered CXCL8 mutant protein (termed PA401) which exhibits a much higher affinity towards GAGs and an impaired GPCR activity. This dominant-negative mutant chemokine showed anti-inflammatory activity in various animal models of neutrophil-driven inflammation, i.e. in urinary tract infection, bleomycin-induced lung fibrosis, and experimental autoimmune uveitis. In all cases, treatment with PA401 resulted in a strong reduction of transmigrated inflammatory cells which became evident from histology sections and bronchoalveolar lavage. Since our CXCL8-based decoy targets GAGs and not GPCRs, our results show for the first time the crucial involvement of this glycan class in CXCL8/neutrophil-mediated inflammation and will thus pave the way to novel approaches of anti-inflammatory treatment.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CXCL8Humanautoimmune uveitis treatmentIMP human recombinant protein in a rat modelRGD 
Cxcl15Mouseautoimmune uveitis treatmentISOCXCL8 (Homo sapiens)human recombinant protein in a rat modelRGD 
CXCL8Humanpulmonary fibrosis treatmentIMP human recombinant protein in a mouse modelRGD 
Cxcl15Mousepulmonary fibrosis treatmentISOCXCL8 (Homo sapiens)human recombinant protein in a mouse modelRGD 
CXCL8Humanurinary tract infection treatmentIMP human recombinant protein in a mouse modelRGD 
Cxcl15Mouseurinary tract infection treatmentISOCXCL8 (Homo sapiens)human recombinant protein in a mouse modelRGD 

Objects Annotated

Genes (Mus musculus)
Cxcl15  (C-X-C motif chemokine ligand 15)

Genes (Homo sapiens)
CXCL8  (C-X-C motif chemokine ligand 8)

Objects referenced in this article
Gene MYD88 MYD88 innate immune signal transduction adaptor Homo sapiens
Gene Myd88 myeloid differentiation primary response gene 88 Mus musculus
Gene Myd88 MYD88, innate immune signal transduction adaptor Rattus norvegicus

Additional Information