Galectin-3 Facilitates Neutrophil Recruitment as an Innate Immune Response to a Parasitic Protozoa Cutaneous Infection

Abstract

When infection occurs, neutrophils rapidly migrate to the affected site. Although the neutrophils neutralize microorganisms, they can also cause tissue damage or render invasion pathways to pathogens. Thus, the migration could be either beneficial or unfavorable in the initial control of infection. Studies on neutrophil recruitment revealed its complexity, especially in terms of the regulation of its initiation. Galectin-3 is a member of the galectin family that has an affinity for β-galactoside containing glycoconjugates. In this study, we investigated the role of galectin-3 in neutrophil migration and the biological significance of the rapid migration of neutrophils in an experimental parasitic cutaneous infection with Leishmania major. When the substrain of L. major, LV39, was infected, lack of galectin-3 impaired neutrophil recruitment in the footpads and the draining lymph nodes 1 d following infection. Reduced number of recruited neutrophils correlated with local high parasite burdens. In contrast, neutrophil migration, induced by the other L. major substrain, Friedlin, was unaffected, and the initial parasite burden remained similar in galectin-3 null mice as compared with wild-type mice. Infection with L. major LV39 but not Friedlin induced higher levels of extracellular release of galectin-3. Further, galectin-3 alone was able to initiate neutrophil migration even though galectin-3 is not a chemoattractant for neutrophils. Thus, our data suggest that once extracellularly released, galectin-3 can act as a damage-associated molecular pattern to facilitate early neutrophil migration, which is beneficial in the initial control of the Leishmania infection.

Leishmania, the phagosome, and host responses: The journey of a parasite

“…Consistent with the abiltiy of GP63 to cleave C3, GP63-deficient L. major promastigotes were shown to be susceptible to complement-mediated lysis [15]. In addition to complement, Galectin-3, a mammalian soluble -galactoside-binding lectin involved in host defense against Leishmania [16,17], was shown to bind to the surface of L. major promastigotes through LPG [18]. Interestingly, bound Galectin-3 is cleaved by GP63 which prevents the formation of high orders of Galectin-3 lattices and may influence the immune response against Leishmania [18,19].…”

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

“…The epithelial damage by the bacteria per se, enhanced by protease expression, induces an augmented inflammatory activation and recruitment of neutrophils, the most important cell type in fighting S. aureus skin infection (3). Neutrophil migration into infected tissue has previously been shown to be affected by galectin-3 (16,50), which is produced in increased amounts during infectious/inflammatory processes (14,16). Neutrophil activation by galectin-3, enhanced after extravasation of the cells into tissue, may contribute to tissue destruction by the production of toxic oxygen radicals and cytokines and the release of neutrophil proteases (15,22,25).…”

“…It exhibits significant regulatory functions both in host defense against infection and in aseptic inflammation (11)(12)(13). Several findings suggest that galectin-3 participates in antimicrobial defense, having opsonizing and bacteriostatic properties or inducing infection-reducing effects in the host (14)(15)(16), but there are also data showing that galectin-3 can contribute to microbial pathogenesis, e.g., by promoting adhesion to host cells or increasing the tissue-destructive response of inflammatory cells (14,15,17,18). Galectin-3 is produced in epithelia and by several immune cells and is released by monocytes and macrophages in response to bacterial lipopolysaccharide (19,20).…”

“…Galectin-3 is produced in epithelia and by several immune cells and is released by monocytes and macrophages in response to bacterial lipopolysaccharide (19,20). The lectin has been proposed to facilitate the transmigration of neutrophils, the most abundant circulating leukocyte, from blood into tissue during the initial steps of inflammation (16,21). Galectin-3 also induces activation of the neutrophil NADPH oxidase, producing reactive oxygen species (ROS) (22,23), and can opsonize apoptotic neutrophils to facilitate their clearance by macrophages (24).…”

New Regulatory Roles of Galectin-3 in High-Affinity IgE Receptor Signaling

“…The N-terminal sequence facilitates oligomerization of Gal3 up to pentamers and can be further organized into complex structures called lattices (45,46). Gal3 plays various roles in immune processes during parasitic infections and allergic inflammation, affecting cytokine production, participating in recruitment of immune cells to inflammatory sites, and regulating Th2 responses (47)(48)(49)(50). Gal3 was originally identified as an IgE-binding protein (51) and has been studied in several cell types, including BMMCs (31,52).…”