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Published on: May 6, 2013
A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes
Sorabh Sharma1, Manjinder Cheema1, Patrick L Reeson1
1Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
Insights
Interleukin-10 (IL-10) exacerbates capillary stalling in the diabetic brain, worsening cognitive impairment. Inhibiting IL-10 signaling in type 1 diabetes reverses these microvascular and cognitive deficits.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Vascular pathology in type 1 diabetes is linked to cognitive impairment.
- Mechanisms of cerebral capillary dysfunction in diabetes are not fully understood.
Purpose of the Study:
- To investigate the role of interleukin-10 (IL-10) in cerebral microcirculatory defects in type 1 diabetes.
- To determine if IL-10 signaling contributes to cognitive impairment in diabetic mice.
Main Methods:
- Examined cerebral capillaries in diabetic mouse models.
- Measured circulating inflammatory cytokines, focusing on IL-10.
- Manipulated IL-10 signaling using neutralizing antibodies and genetic knockdown.
- Assessed cognitive function and cerebral blood flow.
Main Results:
- Diabetic mouse brains exhibited erythrocyte-driven capillary stalling.
- Elevated IL-10 levels were observed in diabetic mice.
- Stimulating IL-10 signaling worsened capillary obstruction.
- Inhibiting IL-10 signaling improved capillary flow, reduced gene expression related to hemostasis and cell adhesion, and reversed cognitive deficits.
Conclusions:
- IL-10 signaling plays a detrimental role in cerebral microvascular dysfunction in type 1 diabetes.
- Targeting IL-10 receptors offers a potential therapeutic strategy for cognitive impairment associated with type 1 diabetes.
Abstract:
Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with type 1 diabetes.
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