Lack of Galectin-3 Disrupts Thymus Homeostasis in Association to Increase of Local and Systemic Glucocorticoid Levels and Steroidogenic Machinery

Abstract

Maintenance of thymus homeostasis is a delicate interplay involving hormones, neurotransmitters and local microenvironmental proteins, as well as saccharides, acting on both thymocytes and stromal cells. Disturbances in these interactions may lead to alterations on thymocyte development. We previously showed that galectin-3, a β-galactoside-binding protein, is constitutively expressed in the thymus, interacting with extracellular matrix glycoproteins and acting as a de-adhesion molecule, thus modulating thymocyte-stromal cell interactions. In this work, we aimed to investigate the participation of galectin-3 in the maintenance of thymus homeostasis, including hormonal-mediated circuits. For that, we used genetically engineered galectin-3-deficient mice. We observed that the thymus of galectin-3-deficient mice was reduced in mass and cellularity compared to wild-type controls; however, the proportions of different thymocyte subpopulations defined by CD4/CD8 expression were not changed. Considering the CD4−CD8− double-negative (DN) subpopulation, an accumulation of the most immature (DN1) stage was observed. Additionally, the proliferative capacity of thymocytes was decreased in all thymocyte subsets, whereas the percentage of apoptosis was increased, especially in the CD4+CD8+ double-positive thymocytes. As glucocorticoid hormones are known to be involved in thymus homeostasis, we evaluated serum and intrathymic corticosterone levels by radioimmunoassay, and the expression of steroidogenic machinery using real-time PCR. We detected a significant increase in corticosterone levels in both serum and thymus samples of galectin-3-deficient mice, as compared to age-matched controls. This was paralleled by an increase of gene transcription of the steroidogenic enzymes, steroidogenic acute regulatory protein (Star) and Cyp11b1 in thymus, 11β-Hydroxysteroid Dehydrogenase (Hsd11b1) in the adrenal, and Cyp11a1 in both glands. In conclusion, our findings show that the absence of galectin-3 subverts mouse thymus homeostasis by a mechanism likely associated to intrathymic and systemic stress-related endocrine circuitries, affecting thymocyte number, proliferation and apoptosis.

Galectin-3: A Novel Marker for the Prediction of Stroke Incidence and Clinical Prognosis

“…Amongst the many complex glycan-protein interactions which govern numerous intracellular processes, galectins serve a variety of important functions [ 4 ]. Galectins are abundantly expressed in many tissues, including gastrointestinal epithelial cells [ 5 , 6 ], the adventitia of blood vessels [ 7 ], fibroblasts [ 8 ], thymocytes [ 9 ], leukocytes [ 10 ], and neuroglial cells [ 11 ]. Numerous biological functions are attributed to the expression of galectins including the recognition of cell damage, adherens junction formation, and cell growth regulation.…”

The Thymus in Chagas Disease: Molecular Interactions Involved in Abnormal T-Cell Migration and Differentiation

“…Additionally, thymocytes from infected mice showed an enhanced Gal-3 gene expression and increased cytoplasmatic protein storage ( 12 ), suggesting that the accumulation of Gal-3 may be associated with the depletion of DP thymocytes. Moreover, thymuses from Gal-3 knockout mice showed diminished cellularity than wild type mice, but the proportions of thymocyte subsets are maintained ( 12 , 80 ). When infected, and despite the low thymic cellularity exhibited by Gal-3 knockout mice, DP thymocyte proportions were preserved as compared to wild-type mice ( 12 , 80 ).…”

“…Moreover, thymuses from Gal-3 knockout mice showed diminished cellularity than wild type mice, but the proportions of thymocyte subsets are maintained ( 12 , 80 ). When infected, and despite the low thymic cellularity exhibited by Gal-3 knockout mice, DP thymocyte proportions were preserved as compared to wild-type mice ( 12 , 80 ). Therefore, understanding the exact role of Gal-3, as well as other pro-apoptotic family members like Gal-1, in thymic atrophy during T. cruzi infection requires further studies.…”

Unraveling How Tumor-Derived Galectins Contribute to Anti-Cancer Immunity Failure

“…Endogenous galectin-3 is another member with an important modulation role in thymocyte development. Indeed, thymocyte subpopulations in galectin-3-deficient mice show a reduction in thymus cellularity, which is due to reduced in vivo proliferation and increased apoptosis of thymocytes [ 155 ]. Interestingly, although exogenous galectin-3 induces T cell apoptosis, the absence of endogenous galectin-3 also induces thymocyte apoptosis.…”