Suppression of Neuropathy Development in Diabetic Rage-Deficient Mice Is Associated with Absence of M1/M2 Macrophage Skewing in the Sciatic Nerve

Abstract

Infiltrating macrophage (Mφ) into sciatic nerve (SN) is assumed one of the pathogenesis of diabetic polyneuropathy (DPN). In particular, skewing infiltrating Mφ toward pro-inflammatory (M1) Mφ, but not anti-inflammatory (M2) Mφ, possibly contributes to dysfunction of SN in diabetic state. However, the impacts of Mφ into dorsal root ganglia (DRG) in DPN are not yet well explored. For this purpose, male C57BL/6 mice (W) and receptor for AGEs (RAGE) null mice (R) were recruited and rendered diabetic (D) with STZ injection. After 8 weeks, nerve conduction velocity (NCV) and tail flick test were performed. Subsequently, mice were sacrificed to dissect SN and DRG, which were evaluated in the pathology and mRNA expression by qPCR. WD showed significant delay of NCV and increase in threshold for thermal sensation (p<0.01), while those were maintained in RD. Pathological analysis elucidated decrease in the average size of cell bodies in the DRG neuron of WD compared to W (p<0.01), as well as the expression of CGRP in DRG neurons (p<0.01). RD maintained neuronal cell size and CGRP expression. Significant increase in infiltration of Iba-I positive Mφ emerged in SN of WD compared to W (p<0.05). The increase was more robust, composed mostly of M2 in RD than WD (p<0.01). No increase of Mφ infiltration was identified in DRG of diabetic groups. The expression of iNOS (a marker for M1) was increased in SN of WD compared to W (p < 0.01), but not in that of RD. The expression of Arg1 (a marker for M2) was significantly increased in SN of RD compared to WD (p < 0.01). However, no changes of iNOS and Arg1 expression were detected in DRG. Our results suggest that proinflammatory changes in distal nerve elicits systematic sensory neuropathy in diabetes and correction of M1φ/M2φ imbalance may be beneficial for its prevention. Disclosure S. Osonoi: None. H. Mizukami: Research Support; Self; Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corporation. S. Ogasawara: None. K. Takahashi: None. K. Sango: None. S. Yagihashi: None.