Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

Abstract

Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-κB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-κBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-κB and NF-κB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-κB activation was blunted in RAGE-null (RAGE -/-) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE -/-mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-κB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Remarkably, in each of these models, protection from development of the pathological features was more profound in wild-type mice treated with sRAGE than in Rage −/− mice. In diabetic neuropathy for example, diabetic Rage −/− mice were only partly protected from a loss of pain perception, while administration of sRAGE to diabetic wild-type mice completely restored pain perception [11]. These observations further suggest that ligands sequestered by sRAGE are likely to interact with cellular structures different from RAGE and restrict its role inasmuch as RAGE seems to be only one of many receptors contributing to diabetes and its complications.…”

“…Ligation of RAGE results in a constantly growing and renewable pool of de novo synthesised, transcriptionally active p65, thereby amplifying the host response [9]. This feed-forward loop has been demonstrated in vitro and in vivo [9,11] (Fig. 3).…”

“…Immunhistochemical characterisation of human inflammatory cells, vascular tissues, kidneys, nerves and retina has clearly demonstrated the accumulation of AGE in human diabetic tissue and its correlation with the severity of disease [6,7]. So far, however, only a few studies have provided firm evidence of colocalisation of AGE with RAGE, its effector NF-κB and NF-κB-controlled gene expression, as recently demonstrated in human sural nerve biopsies from diabetes patients [11]. In any case, these studies can only provide evidence of association, but do not prove a cause-to-consequence relation.…”

“…Similar changes were observed in diabetic neuropathy. Whereas RAGE-transgenic diabetic mice showed an increase in functional deficits such as delayed motor nerve conduction velocity, Rage −/− mice were partially protected from the diabetes-induced loss of neuronal function [11,100]. In the diabetic retina, RAGE is predominantly upregulated in glia cells [101].…”

“…RAGE does not promote the uptake and removal of AGE, but AGE-ligation to RAGE induces inflammation through persistent activation of the proinflammatory transcription factor, nuclear factor kappa-B (NF-κB) [8,9]. When Rage −/− mice were generated [10][11][12] and studied in different pathologies, it became apparent that RAGE is involved in a number of diseases of the innate immune system and RAGE was redefined as a promiscuous pattern recognition receptor (PRR), mediating immune and inflammatory responses, promotion and progression of cancer [13,14], and micro-as well as macrovascular disease [2][3][4][5] by binding a variety of ligands released by inflammatory, stressed and damaged cells [8,15,16]. Subsequently, RAGE×ligand interaction has been associated with survival of RAGE-producing cells, production of cellular reactive oxygen species (ROS), increased levels of phosphorylated extracellular signal-regulated kinase (ERK)1/2, new synthesis of p65 (also known as RelA), NF-κB activation and sustained inflammation [8,15,17,18].…”