Elsevier

Clinical Immunology

Volume 130, Issue 1, January 2009, Pages 83-88
Clinical Immunology

Targeted disruption of the galectin-3 gene results in decreased susceptibility to multiple low dose streptozotocin-induced diabetes in mice

https://doi.org/10.1016/j.clim.2008.08.024Get rights and content

Abstract

Galectin 3 (Gal-3) is an antiapoptotic and a proinflammatory lectin. We hypothesized that the proinflammatory properties of Gal-3 may influence disease induction in the multiple low doses of streptozotocin model of diabetes. Diabetes was induced in C57BL/6 Gal-3+/+ and Gal-3−/− mice and disease monitored by blood glucose level, immuno-histology, insulin content of islets and expression of the proinflammatory cytokines, TNF-α, IFN-γ, IL-17, and iNOS in pancreatic lymph nodes. Gal-3+/+ mice developed delayed and sustained hyperglycemia, mononuclear cellular infiltration and reduced insulin content of islets accompanied with expression of proinflammatory cytokines. Gal-3−/− mice were relatively resistant to diabetogenesis as evaluated by glycemia, quantitative histology and insulin content. Further, we observed the weaker expression of IFN-γ and complete absence of TNF-α, and IL-17 in draining pancreatic lymph nodes. Macrophages, the first cells that infiltrate the islet in this model of diabetes, produce less TNF-α and NO in Gal-3−/− mice. Thus, Gal-3 is involved in immune mediated β cell damage and is required for diabetogenesis in this model of disease.

Introduction

Galectins are animal lectins defined by shared consensus amino acid sequences and affinity for β galactose-containing oligosaccharides [rev in [1], [2]]. Galectins have been shown to influence different interactions in innate and adaptive immune responses [reviewed in [3]]. Galectins 1 and 3, the most widely studied members of a family of 15 lectins identified thus far, are expressed by thymic stromal cells, activated T cells and inflammatory macrophages [3]. It also appears that expression of galectins is regulated according to the activation state of the cells in which they are found [4]. Additionally, it appears that galectin-3 (Gal-3) can have directionally opposite effects, either stimulating or inhibiting cell death depending on whether the protein is located intracellularly or is in the extracellular compartment [5], [6].

It is argued that there is functional cross-talk between Gal-1 and Gal-3 [3] and while (Gal-1) may be a negative regulator of immune responses ameliorating autoimmune encephalomyelitis (EAE) [7], arthritis [8], colitis [9] and hepatitis [10], the role of Gal-3 in autoimmunity in general and type -1 diabetes in particular, is less clear. The establishment of Gal-3−/− mice on a C57BL/6 background [11] offers an opportunity to study the role of Gal-3 in the development of multiple low dose streptozotocin-induced diabetes (MLD-STZ) [12]. The MLD-STZ model has already been used to study the role of nitric oxide (NO) [13], cytokines [14] and transcription factor NF-κB [15] in the pathogenesis of experimental type 1 diabetes mellitus.

In this study, using Gal-3−/− mice, we provide evidence that the absence of galectin-3 profoundly attenuates the development of MLD-STZ diabetes as evaluated by clinical and histological criteria and insulin content of islets. Mitogen-stimulated lymph node cells expressed similar level of cytokine production in Gal-3−/− and Gal-3+/+ mice. However Gal-3−/− exhibited lower expression of disease promoting cytokines by peritoneal macrophages and by immune cells in draining pancreatic lymph nodes after disease induction.

Section snippets

Mice

Gal-3−/− mice were generated as previously detailed by Hsu et al. [11]. Both Gal-3+/+ and Gal-3−/− animals were maintained in the animal facilities at the FMHS, Al Ain and 10–12 week old male mice were used in all experiments. Ethical approval was obtained from the FMHS Animal Research Ethics Committee.

Diabetes induction and evaluation and CFA treatment

Streptozotocin was dissolved in citrate buffer (pH 4.5) and administered intraperitoneally at a dose of 40 mg/kg/day for 5 consecutive days. Blood glucose levels were determined weekly for up to

Gal-3−/− mice are resistant to the induction of MLD-STZ diabetes

We first tested the susceptibility of C57BL/6 mice to the induction of diabetes after the injection of 40 mg STZ/kg for 5 consecutive days (data not shown). They developed progressive and sustained hyperglycemia starting by day 10 after the last STZ injection. We then tested susceptibility to MLD-STZ diabetes induction in C57 BL/6 Gal-3+/+ and Gal-3−/− mice. In repeated experiments, Gal-3−/− mice proved to be much less susceptible to the diabetogenic action of STZ. As shown in Fig. 1, blood

Discussion

In this paper we have demonstrated for the first time that the lack of Gal-3 induced resistance to the induction of MLD-STZ diabetes in a susceptible strain of mice. This resistance was associated with lack of significant mononuclear infiltration in the pancreatic islets and the retention of a higher insulin content when compared with diseased Gal-3+/+ mice.

Recent work by Karlsen et al. [24] demonstrated that overexpression of Gal-3 protects β cells from interleukin 1β mediated apoptosis.

Acknowledgments

This work was supported by Sheikh Hamdan Award for Medical Sciences. We are thankful to Ms. Dawood for secretarial help.

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