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Regulation of Eosinophilia and Allergic Airway Inflammation by The Regulation of eosinophilia and allergic airway PNAS PLUS inflammation by the glycan-binding protein galectin-1 Xiao Na Gea, Sung Gil Haa, Yana G. Greenberga, Amrita Raoa, Idil Bastana, Ada G. Blidnerb, Savita P. Raoa, Gabriel A. Rabinovichb,c,1, and P. Sriramaraoa,d,1,2 aDepartment of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108; bLaboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428ADN Buenos Aires, Argentina; cFacultad de Ciencias Exactas y d Naturales, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina; and Department of Medicine, University of Minnesota, Minneapolis, SEE COMMENTARY MN 55455 Edited by Jorge Geffner, UBA-CONICET, Buenos Aires, Argentina, and accepted by Editorial Board Member Lawrence Steinman June 13, 2016 (received for review February 4, 2016) Galectin-1 (Gal-1), a glycan-binding protein with broad antiinflamma- morphonuclear cells (PMNs), macrophages, dendritic cells tory activities, functions as a proresolving mediator in autoimmune (DCs), activated T cells, stromal cells, endothelial cells, and and chronic inflammatory disorders. However, its role in allergic epithelial cells (5, 6). At a cellular level, Gal-1 may act either airway inflammation has not yet been elucidated. We evaluated the intracellularly or extracellularly, and is profoundly involved in effects of Gal-1 on eosinophil function and its role in a mouse model resolving acute and chronic inflammation by affecting processes of allergic asthma. Allergen exposureresultedinairwayrecruitment such as immune cell adhesion, migration, activation, signaling, of Gal-1–expressing inflammatory cells, including eosinophils, as well proliferation, differentiation, and apoptosis (5, 7). Increasing evi- as increased Gal-1 in extracellular spaces in the lungs. In vitro, extra- dence from multiple chronic inflammatory disease models sup- cellular Gal-1 exerted divergent effects on eosinophils that were ports the critical antiinflammatory role of exogenous and N-glycan– and dose-dependent. At concentrations ≤0.25 μM, Gal-1 endogenous Gal-1 in limiting or resolving inflammation (6). Addi- increased eosinophil adhesion to vascular cell adhesion molecule-1, tionally, Gal-1 showed proresolving effects in models of acute in- caused redistribution of integrin CD49d to the periphery and cell flammation where neutrophil recruitment (8) and extravasation (9) clustering, but inhibited ERK(1/2) activation and eotaxin-1–induced as well as mast cell degranulation were suppressed (9). The im- migration. Exposure to concentrations ≥1 μMresultedinERK(1/2)- munosuppressive role of Gal-1 was further supported by studies dependent apoptosis and disruption of the F-actin cytoskeleton. At with Tregs where cells from Gal-1 null mice exhibited reduced lower concentrations, Gal-1 did not alter expression of adhesion mol- regulatory activity (10). More recent studies emphasized the ecules (CD49d, CD18, CD11a, CD11b, L-selectin) or of the chemokine immunosuppressive effect of Gal-1 in macrophages and cells of receptor CCR3, but decreased CD49d and CCR3 was observed in the microglia compartment, which showed a shift toward an M2 eosinophils treated with higher concentrations of this lectin. In vivo, phenotype and reduced secretion of proinflammatory cytokines allergen-challenged Gal-1–deficient mice exhibited increased recruit- upon exposure to this lectin (11). ment of eosinophils and CD3+ T lymphocytes in the airways as well as Given the critical antiinflammatory and proresolving function elevated peripheral blood and bone marrow eosinophils relative to of Gal-1 in innate and adaptive immune compartments and its broad corresponding WT mice. Further, these mice had an increased pro- expression in lung tissue, we hypothesized that this endogenous lectin might regulate eosinophil function and airway inflammation. pensity to develop airway hyperresponsiveness and displayed signif- icantly elevated levels of TNF-α in lung tissue. This study suggests that Gal-1 can limit eosinophil recruitment to allergic airways and sup- Significance presses airway inflammation by inhibiting cell migration and promot- ing eosinophil apoptosis. Allergic asthma is a chronic airway disease, and the number of individuals with asthma continues to grow. Eosinophils recruited to galectin-1 | eosinophils | apoptosis | migration | allergic airway allergic airways contribute significantly to airway inflammation via inflammation release of proinflammatory mediators that cause epithelial tissue damage, bronchoconstriction, and airway remodeling. Here we llergic asthma is an inflammatory disease of the airways that show that galectin-1 (Gal-1), an endogenous immunoregulatory Ais associated with increased pulmonary recruitment of in- lectin, binds to eosinophil-expressed surface glycans to inhibit cell flammatory cells, especially eosinophils, elevated levels of Th2 migration and induce apoptosis. Using a mouse model of allergic cytokines, proinflammatory chemokines, and growth factors that asthma, we show that mice lacking Gal-1 exhibit increased airway together contribute to the overall pathogenesis of the disease eosinophils and airway hyperresponsiveness compared with wild- including the development of bronchoconstriction and airway type mice. Because Gal-1 plays an important role in regulating hyperresponsiveness (AHR) (1). This disease is to a large extent airway inflammation, identifying pathways to induce Gal-1 syn- driven by activation of Th2 cells and airway eosinophilia. Fur- thesis and/or favor its biological activity might enable exploitation ther, decreased number and/or function of regulatory T cells of its proresolving function to suppress allergic asthma. (Tregs) is also thought to contribute to atopic allergic disease Author contributions: S.P.R., G.A.R., and P.S. designed research; X.N.G., S.G.H., Y.G.G., and asthma in patients (2). Although various therapeutic ap- A.R., and I.B. performed research; A.G.B. contributed new reagents/analytic tools; X.N.G., proaches targeting T cells or cytokines and chemokines released S.G.H., Y.G.G., A.R., I.B., S.P.R., and P.S. analyzed data; and X.N.G., S.P.R., G.A.R., and P.S. by these cells have been developed, positive outcomes are either wrote the paper. limited to small subpopulations (3) or vary significantly among The authors declare no conflict of interest. patient groups, thus warranting the need for identification of This article is a PNAS Direct Submission. J.G. is a guest editor invited by the Editorial novel or alternate therapeutic approaches. Board. Galectin-1(Gal-1)isaglycan-bindingproteinthatbindsto See Commentary on page 9139. N-acetyl-lactosamine (Gal-β1-3/4-N-acetyl-D-glucosamine or LacNAc) 1G.A.R. and P.S. share senior authorship. residues of complex N- and O-glycans on cell-surface glyco- 2To whom correspondence should be addressed. Email: [email protected]. conjugates (4). Gal-1 has wide distribution in adult tissue including This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. INFLAMMATION IMMUNOLOGY AND the lung, and is expressed by various cell types such as poly- 1073/pnas.1601958113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1601958113 PNAS | Published online July 25, 2016 | E4837–E4846 Downloaded by guest on September 26, 2021 Clinical studies have shown that sputum leukocytes (largely that Gal-1 expression by eosinophils (nonactivated) was detectable macrophages) from asthmatic patients have decreased intracel- only when cells were permeabilized (Fig. 2B, Right), with no lular Gal-1 relative to cells from healthy subjects, suggesting that positive staining for this lectin under nonpermeabilized condi- decreased Gal-1 expression might favor exacerbation of asthma tions (Fig. 2B, Left). This suggests that in resting eosinophils, (12). In the present study, we examined the regulated expres- Gal-1 is expressed intracellularly but is undetectable on the cell sion and biological relevance of endogenous and exogenous/ surface. Further, IF staining of permeabilized eosinophils in- extracellular Gal-1 in eosinophil function in vitro and in a model dicated that Gal-1 was predominantly expressed in the cytosolic of allergic asthma. compartment (Fig. 2C). Because allergen exposure results in increased Gal-1 expres- Results sion in extracellular spaces (Fig. 1A), it is likely that eosinophils Expression of Gal-1 Is Induced in Allergic Lungs. We examined the recruited to the airways are exposed to Gal-1 extracellularly. We expression of Gal-1 in the lungs during allergic inflammation in a found that soluble recombinant Gal-1 (rGal-1) binds to the mouse model. In control mice, baseline Gal-1 expression was surface of eosinophils in a dose-dependent fashion (Fig. 2D, observed mostly in airway epithelial cells, smooth muscle cells, Left). Exposure to rGal-1 in the presence of increasing concen- and endothelial cells by immunohistochemistry (IHC; Fig. 1A, trations of lactose, a specific disaccharide inhibitor, but not Upper, Left and Middle). Acute or chronic ovalbumin (OVA) maltose (negative control), inhibited Gal-1 binding to the cell exposure resulted in increased Gal-1 expression in the lungs that surface, indicating that Gal-1 binds to surface ligands on eosin- was largely observed in the recruited inflammatory cells in ad- ophils in a carbohydrate-dependent manner (Fig. 2D, Right). dition to expression in airway epithelial cells, smooth muscle Intracellular (protein
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