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* Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; and
Section of Microbiology, Immunology, and Glycobiology, Department of Laboratory Medicine and
Department of Organic Chemistry, University of Lund, Lund, Sweden
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-
/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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust, U.K. (Clinical Training Fellowship to N.C.H. and Senior Research Leave Fellowship to T.S.), the Medical Research Council, U.K. (Clinical Training Fellowship to P.S.H and Ph.D. studentship to S.L.F.), the Swedish Research Council (Vetenskpasrådet), and by the Swedish Foundation for Strategic Research (to H.L. and U.N.).
2 A.C.M. and S.L.F. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Tariq Sethi, University of Edinburgh, Queen’s Medical Research Institute, 49 Little France Crescent, Edinburgh EH16 4TJ, U.K. E-mail address: t.sethi{at}ed.ac.uk
4 Abbreviations used in this paper: NOS2, NO synthase 2; BMDM, bone marrow-derived macrophage; IL-4R
, IL-4 receptor -chain; PBM, peripheral blood monocyte-derived macrophage; PBS, phosphate-buffered saline; PI(3,4,5)P3, phosphatidylinositol-3,4,5-triphosphate; PI3K, phosphatidylinositol 3-kinase; PKB, protein kinase B; NOS2, nitric oxide synthetase 2; MGC, multinucleated giant cell; WT, wild type.
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