The beta-galactoside binding immunomodulatory lectin galectin-3 reverses the desensitized state induced in neutrophils by the chemotactic peptide f-Met-Leu-Phe: role of reactive oxygen species generated by the NADPH-oxidase and inactivation of the agonist.
Neutrophils interacting with a chemoattractant gradually become nonresponsive to further stimulation by the same agonist, a process known as desensitization. Receptor desensitization is a highly regulated process that involves different mechanisms depending on which receptor-ligand pair that is studied. Galectin-3, a member of a large family of beta-galactoside-binding lectins, has been suggested to be a regulator of the inflammatory process, augmenting or directly triggering the neutrophil functional repertoire. We show here that the desensitized state of neutrophils interacting with the chemotactic peptide fMLF is broken by galectin-3 and that this is achieved through an oxygen radical-mediated inactivation of the chemoattractant. The effect was inhibited by the competitor lactose and required the affinity of galectin-3 for N-acetyllactosamine, a saccharide typically found on cell surface glycoproteins. The latter was shown using a galectin-3 mutant that lacked N-acetyllactosamine binding activity, and this protein was not active. The mechanism behind the inactivation of the chemoattractant was found to depend on the ability of galectin-3 to induce a neutrophil generation/secretion of reactive oxygen species which in combined action with myeloperoxidase inactivated the peptides.
Forsman
Huamei
H
Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden.
Salomonsson
Emma
E
Onnheim
Karin
K
Karlsson
Jennie
J
Björstad
Ase
A
Leffler
Hakon
H
Bylund
Johan
J
Karlsson
Anna
A
Dahlgren
Claes
C
D001665:Binding Sites; D004789:Enzyme Activation; D005697:Galactosides / Q000378:metabolism; D037502:Galectin 3 / Q000378:metabolism / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology*; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D005697:Galactosides; D037502:Galectin 3; D007155:Immunologic Factors; D017382:Reactive Oxygen Species; C007816:beta-galactoside; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019255:NADPH Oxidases