Schwann cell interactions with axons and microvessels in diabetic neuropathy

Abstract

The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annually. The most common complication of diabetes is peripheral neuropathy, which has a prevalence as high as 50% and is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of diabetic neuropathy remain poorly understood, impeding the development of targeted therapies to treat nerve degeneration and its most disruptive consequences of sensory loss and neuropathic pain. Involvement of Schwann cells has long been proposed, and new research techniques are beginning to unravel a complex interplay between these cells, axons and microvessels that is compromised during the development of diabetic neuropathy. In this Review, we discuss the evolving concept of Schwannopathy as an integral factor in the pathogenesis of diabetic neuropathy, and how disruption of the interactions between Schwann cells, axons and microvessels contribute to the disease.

Figure 1 |. Pathogenesis of diabetic neuropathy.

Diabetic neuropathy has a complex pathogenesis involving interaction of axonopathy, schwannopathy and microvasculopathy. The figure shows the anatomical organization of myelinated and unmyelinated axons within nerve fascicles. Their nutrient supply is secured via endoneurial capillaries which, together with the perineurial membrane, form the blood–nerve barrier. a | Human skin biopsy samples immunostained with PGP9.5 to show progression of peripheral nerves from the dermis into the epidermis, where they exist as small unmyelinated C-fibres (scale bar 40 μm). Left panel shows loss of fibres in a patient with diabetic neuropathy and right panel shows fibres in a healthy individual. b | Changes in axons and myelin in diabetic neuropathy, showing degeneration of Schwann cells and nerve fibres, culminating in nerve and intraepidermal fibre loss. c | Endoneurial capillaries from patients with diabetes. Top panel shows a capillary from a patient without diabetic neuropathy, and bottom panel shows a capillary from a patient with neuropathy, in which endothelial cell hyperplasia and basement membrane thickening have reduced the size of the capillary lumen. d | Narrowing of individual capillaries might not prevent blood from passing through the endoneurial capillary bed per se, but the resulting increase in velocity of blood through endoneurial functional shunts or epineurial arteriovenous shunts prevents efficient oxygen extraction, causing hypoxia. Panel a courtesy of Dr Páll Karlsson, Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Denmark.

Figure 2 |. Hyperglycaemia-driven Schwann cell stress and neurodegeneration.

Hyperglycaemia and dyslipidaemia ultimately lead to reduction of neuronal support from Schwann cells and microvessels. In Schwann cells, RAGE (receptor for advanced glycosylation end products) signalling leads to increased glucose metabolism by aldose reductase, which generates local oxidative damage, causes inflammation and drives cells to an immature phenotype. It also affects mitochondrial function, which increases oxygen consumption, and reduces production of desert hedgehog (DHH), which affects endothelial cell function. Endothelial cells also express aldose reductase, and increased polyol pathway flux activates proinflammatory and prothrombotic pathways that reduce nerve blood flow. Disruption of neuronal support by Schwann cells and the vascular system contributes to neuropathy, in conjunction with the direct effects of diabetes on neurons themselves.