Fibronectin Receptor Defects in NOD Mouse Leucocytes: Possible Consequences for Type 1 Diabetes

Abstract

Integrins of the very late antigen (VLA) family mediate leucocyte traffic to lymphoid organs under physiological conditions and in chronic inflammatory situations such as autoimmunity. Accordingly, the current thinking is of a positive correlation between VLA expression and capability of the generation of autoimmunity. Herein we discuss recent findings on the defective expression of integrin-type fibronectin receptors a4b1 (VLA-4) and a5b1 (VLA-5) in the non-obese diabetic (NOD) mouse, a murine model of autoimmune insulindependent diabetes mellitus. As compared with normal animals, NOD thymocytes (including the CD4 þ CD25 þ regulatory T cells) exhibit a decrease in the membrane expression of a5b1, resulting in a functional impairment of fibronectin-mediated interactions, including cell migration. Interestingly, thymocytes that are trapped within the giant perivascular spaces seen in NOD thymus are consistently a5b1 negative, suggesting that the progressive arrest of mature cells can be related to the a5b1 defect. Peripheral T cells also exhibit decreased a5b1 membrane expression and impaired fibronectin-driven migration. Additionally, we observed a defect in a4b1 fibronectin receptor expression in NOD macrophages. Peritoneal, bone marrow-derived-precursor, as well as thymic macrophages of NOD mice showed an impaired upregulation of a4-integrin chain expression, dependent on the level of macrophage maturation. Overall these data lead to the notion that NOD leucocytes bear distinct fibronectin receptormediated cell migration defects, which may be involved in the pathogenesis and/or pathophysiology of the autoimmune events seen in NOD mice. Further studies will be helpful to define whether or not this concept can be applied for other autoimmune diseases.

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

“…We thus evaluated NOD thymocyte migration toward these stimuli. We previously showed that thymocytes from 8-to 10-wk-old NOD mice migrate less than thymocytes from BALB/c and C57BL/6 mice toward fibronectin, an alteration related to the VLA-5 expression defect (9,10). This was confirmed herein in older 12-to 15-wk-old animals (Fig.…”

“…Accordingly, NOD thymocytes present a defect in the membrane expression of VLA-5 (the ␣ 5 ␤ 1 integrin or CD49e/ CD29, a fibronectin receptor), being first observed in late CD4 Ϫ CD8 Ϫ double-negative cells and more pronounced in mature CD4 and CD8 single-positive subsets. Importantly, NOD thymocyte adhesion to thymic epithelial cells or to fibronectin is diminished; the fibronectin-driven migration of NOD thymocytes is significantly impaired and the giant PVS are filled with VLA-5-negative thymocytes that accumulate in these areas (9,10). Rather surprisingly, however, intrathymic FITC injection, which allows the identification of FITC-stained recent thymic emigrants in peripheral lymphoid organs, showed similar rates of thymocyte emigration in NOD recent thymic emigrants when compared with controls (9), indicating that other cell migrationrelated ligands and receptors might be also involved in driving NOD thymocyte migration.…”

Thymic microenvironmental alterations in experimentally induced diabetes

“…Furthermore, CXCL12 and CCR9 are considered as anti-apoptotic molecules (Geutskens et al, 2004) and interestingly, both molecules showed intense decrease here. Moreover, it is important to stress the close relation among hormones, diabetes and thymus.…”

“…Otherwise, in the alloxan-induced diabetes model we showed no alterations in fibronectin density and intense CXCL12 decrease but CXCR4 expression was not down regulated. The presence of CXCL12 secreted by TECs is fundamental for DN thymocyte migration from the cortical-medullar junction to the subcapsular region where these cells become DP and start CCR9 expression enabling them to migrate towards the medulla (Geutskens et al, 2004;Petrie and Zú ñ iga-Pflücker, 2007). In our model, both CCR9 and its ligand (CCL25) decreased and this fact may alter intrathymic migration and T cell maturation, leading as a consequence to a novel histological reorganization of thymus.…”

Fibronectin-α4β1 Integrin Interactions Regulate Metalloproteinase-9 Expression in Steatotic Liver Ischemia and Reperfusion Injury

“…10,37 Cellular FN, which is mostly absent in normal adult tissues, is present in several matrices under tissue pathological conditions, including organ transplantation. 28 A role for FN-mediated leukocyte migration has been previously shown by others in skin inflammation, 39 rheumatoid arthritis, 40 diabetes 41,42 and by us in cardiac transplants. 8 Cellular FN is expressed by sinusoidal endothelial cells very early after liver injury.…”