RAGE activation in macrophages and development of experimental diabetic polyneuropathy
Sho Osonoi, Hiroki Mizukami, Yuki Takeuchi, Hikari Sugawa, Saori Ogasawara, Shizuka Takaku, Takanori Sasaki, Kazuhiro Kudoh, Koichi Ito, Kazunori Sango, Ryoji Nagai, Yasuhiko Yamamoto, Makoto Daimon, Hiroshi Yamamoto, Soroku Yagihashi
Sho Osonoi, Hiroki Mizukami, Yuki Takeuchi, Hikari Sugawa, Saori Ogasawara, Shizuka Takaku, Takanori Sasaki, Kazuhiro Kudoh, Koichi Ito, Kazunori Sango, Ryoji Nagai, Yasuhiko Yamamoto, Makoto Daimon, Hiroshi Yamamoto, Soroku Yagihashi
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Research Article Endocrinology Neuroscience

RAGE activation in macrophages and development of experimental diabetic polyneuropathy

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.

Authors

Sho Osonoi, Hiroki Mizukami, Yuki Takeuchi, Hikari Sugawa, Saori Ogasawara, Shizuka Takaku, Takanori Sasaki, Kazuhiro Kudoh, Koichi Ito, Kazunori Sango, Ryoji Nagai, Yasuhiko Yamamoto, Makoto Daimon, Hiroshi Yamamoto, Soroku Yagihashi

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Figure 8

Disruption of insulin signaling impairs RAT in DRG neurons.

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Disruption of insulin signaling impairs RAT in DRG neurons. (A) Kymograp...
(A) Kymographs of LysoTracker-labeled organelles in axons from dorsal root ganglia (DRG) neurons with 1.0 U/mL insulin. The horizontal and vertical arrows indicate retrograde direction and recording time (4 minutes), respectively. (B–E) The percentage of organelles in 100 μm axon segments that moved anterogradely (B), retrogradely (C), bidirectionally (D), or were stationary (E). n = 18–21 axons from 3 independent experiments. (F) The velocity of retrograde movements (RV) in 100 μm axon segments. The data consisted of 200–300 movements. (G) Kymographs in axons from DRG neurons treated with vehicle and insulin receptor antagonist (BMS-754807, 300 or 500 nmol/L). The stimulation time was 60 minutes. The horizontal and vertical arrows indicate retrograde direction and recording time (4 minutes), respectively. (H–K) The percentage of organelles in 100 μm axon segments that moved anterogradely (H), retrogradely (I), or bidirectionally (J), or were stationary (K). n = 18–21 axons from 3 independent experiments. (L) RV in 100 μm axon segments in each treatment condition. (M) Kymographs in axons from DRG neurons treated with vehicle, TNF-α, and TNF-α + JNK inhibitor (SP600125). The stimulation time was 20 minutes. The vertical arrow indicates recording time (4 minutes). (N–Q) The percentage of organelles in 100 μm axon segments that moved anterogradely (N), retrogradely (O), bidirectionally (P), or were stationary (Q). n = 18–21 axons from 3 independent experiments. (R) RV in 100 μm axon segments. The data consisted of 200–300 movements. The data are presented as the mean ± SD. Because the experiments of G–L and M–R were performed contemporaneously, statistical analysis was done using same vehicle control. Statistical analysis was performed by Student’s 2-tailed unpaired t test for B–F and by 1-way ANOVA with Tukey’s multiple-comparison test for H–L and N–R. **P < 0.01, ***P < 0.001.