Regulation of Alternative Macrophage Activation by Galectin-3
| Autor: | Kirsten M. Atkinson, Hakon Leffler, Alison C. MacKinnon, Philip S. Hodkinson, Christopher Haslett, Ulf J. Nilsson, Sarah L. Farnworth, Stuart J. Forbes, Tariq Sethi, Neil C. Henderson |
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| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
CD98 Galectin 3 Immunology Bone Marrow Cells Fusion Regulatory Protein-1 Monocytes Immunophenotyping Mice Phosphatidylinositol 3-Kinases Cell surface receptor Cell Line Tumor Macrophages Alveolar otorhinolaryngologic diseases Animals Humans Immunology and Allergy Macrophage Secretion Interleukin 4 PI3K/AKT/mTOR pathway Feedback Physiological Mice Knockout Regulation of gene expression biology Macrophages Macrophage Activation Cell biology Enzyme Activation Autocrine Communication Gene Expression Regulation Galectin-3 Macrophages Peritoneal biology.protein Interleukin-4 |
| Zdroj: | The Journal of Immunology. 180:2650-2658 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.180.4.2650 |
| Popis: | 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-γ/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)-β-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. |
| Databáze: | OpenAIRE |
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