Th1 and Th2 cytokines exert regulatory effects upon islet microvascular areas in the NOD mouse

Abstract

In this study, we show that intra- and peri-islet microvascular areas undergo different changes during the islet inflammation in the nonobese diabetes-prone female mice. Actually, although the islet vascular area (IVA) considerably decreases while the infiltration progresses, at 15 weeks of age, the peri-islet vascular bed is unexpectedly and significantly increased. On the contrary, the intra-IVA is significantly decreased, due to vessel dilation. Later, by 20-25 weeks of age, a decrease of both IVA occur, due to a significant islet beta cell loss. Moreover, a dramatic fall of natural free radical scavenger values, which, in turn, exert an influence upon vessels, is observed. These effects are completely counteracted by the administration of IL-4, a Th2 protective cytokine; IL-10, another putative Th2 cytokine, exerts direct effects upon endothelial cell (EC) function, as shown by the increase of endothelial nitric oxide synthase (eNOS) mRNA transcripts and by the release of endothelial NO which, in turn, exert vasodilatory effects; moreover, this cytokine significantly upregulates adhesion molecules on endothelia. On the other hand, IL-1beta, a Th1 proinflammatory cytokine, dramatically increases nitrite and nitrate levels, as well as inducible nitric oxide synthase (iNOS) transcripts and also upregulates islet ICAM-1 expression as well as circulating ICAM-1 levels. Taken together, our findings clearly show that cytokines and islet endothelia are directly involved in the pathophysiology of the disease. Their reciprocal influence gives new insight to understand the role of microvasculature during islet beta cell attack.

Longitudinal three-dimensional visualisation of autoimmune diabetes by functional optical coherence imaging

“…An observed decrease in the vascular density in areas affected by insulitis coincided with a promotion of MAdCAM-1-expressing HEV-like structures. Altered vasculature has previously been associated with type 1 diabetes [2][3][4]36]. More specifically, Villalta et al [36] have reported an increase rather than a decrease in vasculature when comparing pancreases from NOD mice prior to insulitis onset and NOD mice with advanced insulitis.…”

“…Modifications of the pancreatic microvasculature are likely to accompany the progression of both types of diabetes. Alterations in vascular variables, such as transient vasoconstriction, vasodilation, increased blood flow and vascular leakage, are necessary preludes to inflammation as they orchestrate the influx of diverse cell types and affect local homeostasis [1][2][3][4][5][6]. To fully appreciate how these events contribute to the pathogenesis, improved methods allowing longitudinal, highresolution monitoring of vascularisation and affected tissues close to the cellular level during its natural progression are warranted and constitute the key objectives of this study.…”

The impact of anti-inflammatory cytokines on the pancreatic β-cell

“…Hence, numerous studies have revealed that treatment of NOD mice (a rodent model of type 1 diabetes) with IL-4, IL-13 or IL-10 delays the onset of spontaneous diabetes and also reduces its incidence. [20][21][22][23][24] Furthermore, Tcells isolated from the blood of such mice exhibit a more Th2-like phenotype, releasing higher levels of anti-inflammatory cytokines than those of control NOD mice. 22,25 The incidence of diabetes can also be delayed in the NOD mouse by generating animals that specifically express IL-4 in b-cells 26 or by the injection of dendritic cells which constitutively express this cytokine 27 However, other studies have found that overexpression of IL-10 in islet endocrine cells may have little effect on diabetes progression, 28 and in some cases it can accelerate the disease process.…”

“…37 Finally, anti-inflammatory molecules are reported to inhibit changes in the microvasculature associated with diabetes progression in the NOD mouse. 24 Taken together, it can be concluded from such evidence that, while pro-inflammatory factors are likely to be of primary importance in diabetes pathogenesis, any simultaneous reduction in the level of anti-inflammatory cytokines may serve to exacerbate their negative effects on islet cell viability and function.…”

Imaging inflammation of the pancreatic islets in type 1 diabetes

“…Not surprisingly, changes in intraislet vasculature precede streptozotocin-induced insulitis (3)(4)(5)(6) and vascular swelling and modifications of endothelial cell morphology in the paraislet region signal impending insulitis in nonobese diabetic (NOD) mice (7). In both of these diabetes models, and other models, increased blood flow and edema ensue (6,8,9). Such modifications might be detectable by certain of the powerful new methodologies for imaging the microvasculature in rodents and humans described recently (10).…”