Toxoplasma gondii Infection Reveals a Novel Regulatory Role for Galectin-3 in the Interface of Innate and Adaptive Immunity

Abstract

In attempts to investigate the role of galectin-3 in innate immunity, we studied galectin-3-deficient (gal3 ؊/؊ ) mice with regard to their response to Toxoplasma gondii infection, which is characterized by inflammation in affected organs, Th-1-polarized immune response, and accumulation of cysts in the central nervous system. In wild-type (gal3 ؉/؉ ) mice, infected orally, galectin-3 was highly expressed in the leukocytes infiltrating the intestines, liver, lungs, and brain. Compared with gal3 ؉/؉ , infected gal3 ؊/؊ mice developed reduced inflammatory response in all of these organs but the lungs. Brain of gal3 ؊/؊ mice displayed a significantly reduced number of infiltrating monocytes/macrophages and CD8 ؉ cells and a higher parasite burden. Furthermore, gal3 ؊/؊ mice mounted a higher Th1-polarized response and had comparable survival rates on peroral T. gondii infection, even though they were more susceptible to intraperitoneal infection. Interestingly, splenic cells and purified CD11c ؉ dendritic cells from gal3 ؊/؊ mice produced higher amounts of interleukin-12 than cells from gal3 ؉/؉ mice, possibly explaining the higher Th1 response verified in the gal3 ؊/؊ mice. We conclude that galectin-3 exerts an important role in innate immunity, including not only a proinflammatory effect but also a regulatory role on dendritic cells, capable of interfering in the adaptive immune response.

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

“…These results indicate that the bacterial clearance in the early course of R. equi infection was more efficient in gal3 À/À mice compared with gal3 1/1 mice. Gal3 À/À mice develop a delayed but increased inflammatory response compared with gal3 1/1 mice It was previously shown that galectin-3 expression is upregulated during allergic airway inflammation [28] and Toxoplasma gondii infection [29]. Here, we found an increase in galectin-3 staining in the liver and spleen from the gal3 1/1 mice that had been intravenously inoculated with R. equi ( Fig.…”

“…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.…”

“…Interestingly, it has been suggested that galectin-3 regulates both Th1 and Th2 response because gal3 À/À mice developed a lower Th2 response but a higher Th1 response in a murine model of asthma [28]. In fact, we have previously suggested that galectin-3 may act in the regulatory loops controlling Th1 cytokine production, especially by influencing IL-12 production by dendritic cells [29]. Here, we add another piece of evidence that galectin-3 is a tuner of the immune system, being able to adjust the intensity of the immune response by regulating the innate immune response.…”

“…On the other hand, data showing galectin-3 as a negative regulator of adaptive immune response came from studies with galectin-3-deficient mice, which developed a heightened Th1 response in two different experimental models [28,29]. Indeed, we have previously reported that galectin-3 might influence the interface of innate and adaptive immunity by suppressing IL-12 production by dendritic cells [29]. Herein, the lack of galectin-3 was demonstrated to be associated with enhanced resistance to R. equi infection, as indicated by the initial observation of higher survival rate of gal3 À/À mice to the bacterial infection.…”

“…3I). Taken together, these results indicate that gal3 À/À mice exhibited an increased, although delayed, inflammatory response, which may promote a more efficient bacterial clearance and enhanced survival of gal3 À/À mice to R. equi infection.Gal3 À/À mice produce higher IL-12 levels than gal3 1/1 mice Based on the previous demonstration that galectin-3 regulates IL-12 production by APCs [29] and that R. equi is an efficient inducer of IL-12 and TNF-a production by macrophages [27], we measured the serum levels of both cytokines in gal3 1/1 and Immunohistochemical staining for galectin-3 in organs of R. equi-infected wild-type mice. Gal3 1/1 and gal3 À/À mice were intravenously inoculated with R. equi (1 Â 10 6 ), and splenic and liver immunohistochemical studies were performed at several intervals postinfection.…”