Regulation of alternative macrophage activation by galectin-3.
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.
MacKinnon
Alison C
AC
Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 49 Little France Crescent, Edinburgh, United Kingdom.
Farnworth
Sarah L
SL
Hodkinson
Philip S
PS
Henderson
Neil C
NC
Atkinson
Kirsten M
KM
Leffler
Hakon
H
Nilsson
Ulf J
UJ
Haslett
Christopher
C
Forbes
Stuart J
SJ
Sethi
Tariq
T
D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000276:immunology; D025461:Feedback, Physiological / Q000276:immunology; D027261:Fusion Regulatory Protein-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D037502:Galectin 3 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology
D027261:Fusion Regulatory Protein-1; D037502:Galectin 3; D008070:Lipopolysaccharides; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases