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Published on: December 7, 2017
RAGE activation in macrophages and development of experimental diabetic polyneuropathy
Sho Osonoi1,2, Hiroki Mizukami1, Yuki Takeuchi1,2
1Department of Pathology and Molecular Medicine and.
Abstract:
It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage-elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.
Insights
Receptor for advanced glycation end products (RAGE) activation drives inflammation in diabetic nerve damage. Blocking RAGE promotes anti-inflammatory macrophages, protecting against diabetic polyneuropathy (DPN) and nerve deficits.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Diabetic polyneuropathy (DPN) involves macrophage infiltration and inflammation.
- The role of the receptor for advanced glycation end products (RAGE) in DPN pathogenesis is not fully understood.
- RAGE activation is linked to proinflammatory responses in diabetic nerve tissues.
Purpose of the Study:
- To investigate the role of RAGE in the pathogenesis of DPN using modified macrophages.
- To clarify the association between macrophage RAGE activation and downstream effects in DPN.
- To explore RAGE as a potential therapeutic target for DPN.
Main Methods:
- Utilized type 1 diabetic mice and RAGE-null mice.
- Performed bone marrow (BM) transplantation experiments.
- Conducted in vitro coculture of primary neuronal cells and macrophages.
- Employed time-lapse recording to assess axonal transport.
Main Results:
- Proinflammatory macrophages in diabetic mice impaired insulin sensitivity, caused neuronal atrophy, and slowed axonal transport.
- RAGE-null mice exhibited anti-inflammatory macrophages, preserved insulin sensitivity, normalized neurons, and maintained axonal transport.
- BM transplantation from RAGE-null to diabetic mice ameliorated peripheral nerve deficits.
- In vitro studies confirmed that proinflammatory macrophages induce insulin resistance and axonal transport deficits.
Conclusions:
- RAGE is a key determinant of macrophage polarization in DPN.
- Targeting RAGE may offer a novel therapeutic strategy for DPN.
- RAGE-mediated inflammation significantly contributes to the development of diabetic nerve damage.
