title: The monomer-dimer equilibrium and glycosaminoglycan interactions of chemokine CXCL8 regulate tissue-specific neutrophil recruitment.
abstract: Chemokines exert their function by binding the GPCR class of receptors on leukocytes and cell surface GAGs in target tissues. Most chemokines reversibly exist as monomers and dimers, but very little is known regarding the molecular mechanisms by which the monomer-dimer equilibrium modulates in vivo function. For the chemokine CXCL8, we recently showed in a mouse lung model that monomers and dimers are active and that the monomer-dimer equilibrium of the WT plays a crucial role in regulating neutrophil recruitment. In this study, we show that monomers and dimers are also active in the mouse peritoneum but that the role of monomer-dimer equilibrium is distinctly different between these tissues and that mutations in GAG-binding residues render CXCL8 less active in the peritoneum but more active in the lung. We propose that tissue-specific differences in chemokine gradient formation, resulting from tissue-specific differences in GAG interactions, are responsible for the observed differences in neutrophil recruitment. Our observation of differential roles played by the CXCL8 monomer-dimer equilibrium and GAG interactions in different tissues is novel and reveals an additional level of complexity of how chemokine dimerization regulates in vivo recruitment.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Pavani
authors.initials: P
authors.lastname: Gangavarapu
authors.forename: Lavanya
authors.initials: L
authors.lastname: Rajagopalan
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Antonieta
authors.initials: A
authors.lastname: Guerrero-Plata
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
authors.forename: Krishna
authors.initials: K
authors.lastname: Rajarathnam
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D019281:Dimerization; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009504:Neutrophils / Q000502:physiology*; D009928:Organ Specificity; D010537:Peritoneum / Q000187:drug effects / Q000276:immunology*; D011485:Protein Binding; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms
chemical_list: C508606:CXCL8 protein, human; D006025:Glycosaminoglycans; D016209:Interleukin-8; D011993:Recombinant Fusion Proteins