Galectin-3 interacts with naïve and primed neutrophils, inducing innate immune responses

Abstract

The neutrophil is the first line of defense against infection. As a part of the innate immune response, neutrophils start to emigrate from blood to an affected site and their state is altered from passively circulating naïve to primed, and then to fully activated. The extent of neutrophil activation and their subsequent response varies depending on the stimuli and environment that neutrophils encounter. Because neutrophils can also induce deleterious effects on host tissues, tight regulation of recruitment and functions of neutrophils is required for efficient recovery. Galectin-3, a soluble beta-galactoside binding protein, of which expression is up-regulated during inflammation/infection, is suggested to be involved in various inflammatory responses. However, the precise roles of this lectin in innate immunity remain unknown, while it has been demonstrated that galectin-3 binds to naïve and primed neutrophils. Here we report that galectin-3 can induce L-selectin shedding and interleukin-8 production in naïve and primed neutrophils. These activities were shown to be dependent on the presence of the C-terminal lectin domain and the N-terminal nonlectin domain of galectin-3, which is involved in oligomerization of this lectin. We also found that, after galectin-3 binds to neutrophils, primed but not naïve neutrophils can cleave galectin-3, mainly through elastase, which results in the formation of truncated galectin-3 lacking the N-terminal domain. Together, these results suggest that galectin-3 activates naïve and primed neutrophils, and galectin-3-activated primed neutrophils have an ability to inactivate galectin-3.

Integrin Regulation during Leukocyte Recruitment

“…These findings were confirmed in a mouse model of IL-1b-induced inflammation of the m. cremaster that revealed increased numbers of recruited neutrophils in galectin-1-deficient mice (66). Although galectin-3 has been found to improve the clinical picture of experimental models of LPS-induced inflammation (67), the underlying mechanisms remain unclear, especially because galectin-3 has been shown to possess proinflammatory qualities (68). Resolvins and lipoxins.…”

Functions of cell surface galectin-glycoprotein lattices

“…This lectin binds to multi-glycosylated proteins with positive cooperativity, suggesting that galectin-3 monomers, after ligand binding, recruit additional lectin molecules to form a complex of multivalent interactions [5,13]. The biologic functions attributed to galectin-3 are thus likely to depend upon both ligand cross-linking and oligomerization [6,[14][15][16][17]. The tandem-repeat type galectins have two CRDs connected by a linker peptide and, thus are bivalent, although the two CRDs may be able to recognize different saccharide ligands [6] (Figure 1).…”

“…Galectin-carbohydrate lattices may also modulate the biology of innate immune cells at inflammatory foci [6,15,16]. Galectin-3-mediated ligand clustering triggers neutrophils to phagocytose, produce reactive oxygen species, release proteases, and secrete interleukin (IL)-8 [15,16,30].…”

“…Galectin-3-mediated ligand clustering triggers neutrophils to phagocytose, produce reactive oxygen species, release proteases, and secrete interleukin (IL)-8 [15,16,30]. In addition, galectin-3 induces mast cell degranulation: recent studies have revealed a critical role for this protein in mast cell function since galectin-3-deficient mast cells show reduced histamine release and IL-4 secretion [14].…”

Visualization of Galectin-3 Oligomerization on the Surface of Neutrophils and Endothelial Cells Using Fluorescence Resonance Energy Transfer

“…11-14 and 25-28; for a review, see . It has been reported that proteolytic cleavage of galectin-3, resulting in the removal of the N-terminal domain, prevents galectin-3 from exerting its functions whereas it still binds to its ligands (11)(12)(13)(14)(25)(26)(27)(28). Since most of its functions are thought to depend on oligomerization, the lack of extracellular function of truncated galectin-3 presumably resides in the impossibility for the truncated form to oligomerize.…”