Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow

William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Charterhouse Square, London, UK.
Journal of Leukocyte Biology (Impact Factor: 4.3). 07/2008; 83(6):1459-66. DOI: 10.1189/jlb.1207831
Source: PubMed

ABSTRACT Galectin-1 (Gal-1) is a beta-galactoside-binding protein endowed with anti-inflammatory properties. The purpose of this study was to investigate the effects of endogenous and exogenous Gal-1 on neutrophil recruitment onto TNF-treated endothelium. The effect of human recombinant (hr)Gal-1 on markers of neutrophil activation (CD11b expression, P-selectin glycoprotein ligand 1, and L-selectin shedding) was also assessed. Gal-1 inhibited the platelet-activating factor-induced increase in CD11b expression in a concentration-dependent manner, as assessed by flow cytometry. To determine the effects of Gal-1 on neutrophil recruitment, an in vitro flow chamber was used: Preincubation of neutrophils with hrGal-1 significantly decreased the extent of capture, rolling, and adhesion on activated endothelial monolayers. This inhibition was shared with the endogenous protein, as knockdown of endothelial Gal-1 using small interfering RNA resulted in a significant increase in the number of cells captured and rolling. To verify the effects of Gal-1 in an in vivo system, intravital microscopy of Gal-1 null mice and their wild-type counterparts was performed. Leukocyte adhesion and emigration were increased significantly in the cremasteric circulation of Gal-1 null mice inflamed with IL-1beta. These findings indicate that Gal-1 functions to limit neutrophil recruitment onto a TNF-treated endothelium, a property that may underline its inhibitory effects in acute inflammation.

Download full-text


Available from: Mauro Perretti, Jul 09, 2015
  • Source
    • "Continued leukocyte recruitment might also be caused by malfunctioning of restraining or homeostatic mechanisms. More specifically, a number of endogenous inhibitors of leukocyte recruitment have been described [53], including pentraxin 3 (PTX- 3) [54], developmental endothelial locus-1 (del-1) [55], galectin-1 [56] [57], and growth differentiation factor 15 (GDF-15) [58]. It is therefore reasonable to assume that an inhibition or decreased availability of these factors can contribute to continued leukocyte recruitment. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is commonly looked upon as a chronic inflammatory disease of the arterial wall arising from an unbalanced lipid metabolism and a maladaptive inflammatory response. However, atherosclerosis is not merely an inflammation of the vessel wall. In fact, the cardinal signs of unstable atherosclerotic lesions are primarily characteristics of failed resolution of a chronic inflammation. In contrast to acute inflammatory events which are typically self-limiting, atherosclerosis is an unresolved inflammatory condition, lacking the switch from the pro-inflammatory to the pro-resolving phase, the latter characterized by termination of inflammatory cell recruitment, removal of inflammatory cells from the site of inflammation by apoptosis and dead cell clearance, reprogramming of macrophages toward an anti-inflammatory, regenerative phenotype, and finally egress of effector cells and tissue regeneration. Here we present an overview on mechanisms of failed resolution contributing to atheroprogression and deliver a summary of novel therapeutic strategies to restore resolution in inflamed arteries. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Seminars in Immunology 04/2015; DOI:10.1016/j.smim.2015.03.013 · 6.12 Impact Factor
  • Source
    • "Neutrophils often damage viable tissue during acute inflammatory episodes resulting in loss of intracellular contents (Nathan 2006). Thus, release of Gal-1 during leukocyte-mediated injury may allow Gal-1 to engage leukocytes and therefore be uniquely poised to inhibit their chemotaxis and induce their turnover (Dias-Baruffi et al. 2003; Cooper et al. 2008; Stowell, Arthur, Mehta, et al. 2008; Stowell, Arthur, Slanina, et al. 2008; Stowell, Qian, et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Galectin-1 (Gal-1) is important in immune function and muscle regeneration, but its expression and localization in adult tissues and primary leukocytes remain unclear. To address this, we generated a specific monoclonal antibody against Gal-1, termed alphahGal-1, and defined a sequential peptide epitope that it recognizes, which is preserved in human and porcine Gal-1, but not in murine Gal-1. Using alphahGal-1, we found that Gal-1 is expressed in a wide range of porcine tissues, including striated muscle, liver, lung, brain, kidney, spleen, and intestine. In most types of cells, Gal-1 exhibits diffuse cytosolic expression, but in cells within the splenic red pulp, Gal-1 showed both cytosolic and nuclear localization. Gal-1 was also expressed in arterial walls and exhibited prominent cytosolic and nuclear staining in cultured human endothelial cells. However, human peripheral leukocytes and promyelocytic HL60 cells lack detectable Gal-1 and also showed very low levels of Gal-1 mRNA. In striking contrast, Gal-1 exhibited an organized cytosolic staining pattern within striated muscle tissue of cardiac and skeletal muscle and colocalized with sarcomeric actin on I bands. These results provide insights into previously defined roles for Gal-1 in inflammation, immune regulation and muscle biology.
    Glycobiology 05/2010; 20(5):507-20. DOI:10.1093/glycob/cwp203 · 3.75 Impact Factor
  • Source
    • "This latter effect could explain the high number of PMNs at 24 h in the hrGal-1-treated animals compared to the vehicle group. However, no Gal-1 effect was found on CD62L expression in the studies conducted by Cooper et al. [12], which demonstrated an inhibitory role of hrGal-1 administration in the steps of rolling and firm adhesion of platelet-activating factor (PAF)-stimulated PMNs to endothelial cells by significantly decreasing CD11b expression. The data showed clearly that exogenous Gal-1 downregulates CD11b expression , but its effect on CD62L warrants further investigation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effect of exogenous Gal-1 on cellular response and adhesion molecule expression was investigated in a classical model of acute inflammation induced by zymosan. C57BL6 mice, treated or not with human recombinant (hr) Gal-1, received i.p. injection of zymosan and peritoneal exudate, blood and mesentery were processed for cellular, biochemical, light and electron microscopic analysis after 4 and 24 h. Zymosan peritonitis provoked the expected signs of inflammation at 4 h, including a significant increase in extravasated PMNs in the mesentery and peritoneal exudate, mirrored by blood neutrophilia. These changes subsided after 24 h. Ultrastructural immunocytochemical analysis of PMNs showed significant Gal-1 expression and co-localization with L-selectin and β2-integrin in the plasma membrane and cytoplasm. Pharmacological treatment with hrGal-1 at 4 h produced an inhibition of PMN migration, associated with diminished expression of adhesion molecules, particularly β2-integrin, and TNF-α and IL-1β release by peritoneal cells. At 24 h, Gal-1 induced an increase in mononuclear phagocytic cell recruitment. In conclusion, our data propose an important mechanism of anti-inflammatory action of Gal-1, initially by modulation of pro-inflammatory cytokine release and PMN migration through an imbalance between adhesion molecule expression and, later, by promoting monocyte-macrophage recruitment.
    International journal of clinical and experimental pathology 01/2010; 4(1):74-84. · 1.78 Impact Factor