Targeted Disruption of the Galectin-3 Gene Results in Attenuated Peritoneal Inflammatory Responses

Abstract

Galectin-3 is a member of a growing family of beta-galactoside-binding animal lectins. Previous studies have demonstrated a variety of biological activities for this protein in vitro, including activation of cells, modulation of cell adhesion, induction of pre-mRNA splicing, and regulation of apoptosis. To assist in fully elucidating the physiological and pathological functions of this protein, we have generated galectin-3-deficient (gal3(-/-)) mice by targeted interruption of the galectin-3 gene. Gal3(-/-) mice consistently developed fewer inflammatory cell infiltrations in the peritoneal cavities than the wild-type (gal3(+/+)) mice in response to thioglycollate broth treatment, mainly due to lower numbers of macrophages. Also, when compared to cells from gal3(+/+) mice, thioglycollate-elicited inflammatory cells from gal3(-/-) mice exhibited significantly lower levels of NF-kappaB response. In addition, dramatically different cell-spreading phenotypes were observed in cultured macrophages from the two genotypes. Whereas macrophages from gal3(+/+) mice exhibited well spread out morphology, those from gal3(-/-) mice were often spindle-shaped. Finally, we found that peritoneal macrophages from gal3(-/-) mice were more prone to undergo apoptosis than those from gal3(+/+) mice when treated with apoptotic stimuli, suggesting that expression of galectin-3 in inflammatory cells may lead to longer cell survival, thus prolonging inflammation. These results strongly support galectin-3 as a positive regulator of inflammatory responses in the peritoneal cavity.

Lack of galectin‐3 alters the balance of innate immune cytokines and confers resistance to Rhodococcus equi infection

“…It has been difficult to address the exact mechanism underlying the proinflammatory role of galectin-3. Several authors have reported that the absence of galectin-3 affects the migration of macrophages, eosinophils, neutrophils and lymphocytes in a different way, depending on the experimental conditions [14,28] and the organ examined [29]. In the present study, gal3 À/À mice also exhibited an attenuated inflammatory response in the liver during the first 24-48 h postinfection, which was not associated with higher bacterial burdens.…”

“…Gal3 À/À mice were generated as previously described, and backcrossed to C57BL/6J for at least nine generations [14]. Agematched gal3 1/1 mice obtained from breeding gal3 1/-animals were maintained in parallel with gal3 À/À mice and were used as controls in all the experiments.…”

“…Extracellular galectin-3 is able to activate cells [4][5][6][7][8][9] cell-cell and cell-extracellular matrix interactions [10][11][12], and induce phagocyte migration [13]. However, galectin-3 also functions inside the cells and can contribute to macrophage functions that are essential in the cellular response during the infectious process, such as cell survival [14] and phagocytosis [15].…”

“…Extracellular galectin-3 is able to activate cells [4][5][6][7][8][9] cell-cell and cell-extracellular matrix interactions [10][11][12], and induce phagocyte migration [13]. However, galectin-3 also functions inside the cells and can contribute to macrophage functions that are essential in the cellular response during the infectious process, such as cell survival [14] and phagocytosis [15].As a result of its ability to recognize glycans containing b-galactoside, galectin-3 binds to glycoconjugates synthesized by several pathogens such as Mycobacterium tuberculosis [16], Leishmania major [17], Trypanosoma cruzi [18], Schistosoma mansoni [19] and Candida albicans [20]. Recently, galectin-3 and TLR2 have been found to be associated in C. albicans-infected differentiated macrophages, an association that has been considered essential for TLR2-dependent cytokine production in response to the fungal infection [21].…”

Critical Role for Galectin-3 in Airway Inflammation and Bronchial Hyperresponsiveness in a Murine Model of Asthma

“…Recently, we and others have shown that gal3 Ϫ/Ϫ mice exhibit reduced peritoneal inflammation in response to thioglycollate treatment. 37,38 Based on the demonstrated functions of galectin-3, we hypothesized that this lectin might play a role in the development of airway inflammation, as occurs in asthma. In the present study, we have analyzed the expression and function of galectin-3 in a murine model of asthma, in which mice were sensitized systemically with ovalbumin (OVA) and then challenged with OVA through the airways.…”