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Regulation of alternative macrophage activation by galectin-3.

TitleRegulation of alternative macrophage activation by galectin-3.
Publication TypeJournal Article
Year of Publication2008
AuthorsMackinnon AC, Farnworth SL, Hodkinson PS, Henderson NC, Atkinson KM, Leffler H, Nilsson UJ, Haslett C, Forbes SJ, Sethi T
JournalJ Immunol
Volume180
Issue4
Pagination2650-8
Date Published2008 Feb 15
ISSN0022-1767
KeywordsAnimals, Antigens, CD98, Autocrine Communication, Bone Marrow Cells, Cell Line, Tumor, Enzyme Activation, Feedback, Physiological, Galectin 3, Gene Expression Regulation, Humans, Immunophenotyping, Interleukin-4, Lipopolysaccharides, Macrophage Activation, Macrophages, Macrophages, Alveolar, Macrophages, Peritoneal, Mice, Mice, Knockout, Monocytes, Phosphatidylinositol 3-Kinases
Abstract

Alternative macrophage activation is implicated in diverse disease pathologies such as asthma, organ fibrosis, and granulomatous diseases, but the mechanisms underlying macrophage programming are not fully understood. Galectin-3 is a carbohydrate-binding lectin present on macrophages. We show that disruption of the galectin-3 gene in 129sv mice specifically restrains IL-4/IL-13-induced alternative macrophage activation in bone marrow-derived macrophages in vitro and in resident lung and recruited peritoneal macrophages in vivo without affecting IFN-gamma/LPS-induced classical activation or IL-10-induced deactivation. IL-4-mediated alternative macrophage activation is inhibited by siRNA-targeted deletion of galectin-3 or its membrane receptor CD98 and by inhibition of PI3K. Increased galectin-3 expression and secretion is a feature of alternative macrophage activation. IL-4 stimulates galectin-3 expression and release in parallel with other phenotypic markers of alternative macrophage activation. By contrast, classical macrophage activation with LPS inhibits galectin-3 expression and release. Galectin-3 binds to CD98, and exogenous galectin-3 or cross-linking CD98 with the mAb 4F2 stimulates PI3K activation and alternative activation. IL-4-induced alternative activation is blocked by bis-(3-deoxy-3-(3-methoxybenzamido)-beta-D-galactopyranosyl) sulfane, a specific inhibitor of extracellular galectin-3 carbohydrate binding. These results demonstrate that a galectin-3 feedback loop drives alternative macrophage activation. Pharmacological modulation of galectin-3 function represents a novel therapeutic strategy in pathologies associated with alternatively activated macrophages.

Alternate JournalJ. Immunol.
PubMed ID18250477
Grant List / / Wellcome Trust / United Kingdom