IFN‐γ/mTORC1 decreased Rab11 in Schwann cells of diabetic peripheral neuropathy, inhibiting cell proliferation via GLUT1 downregulation

Abstract

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus. Rab11 is conserved gene‐regulating vesicle traffic and reported to be involved in the pathogenesis of diabetes mellitus by affecting insulin sensitivity. We aimed to investigate the role of Rab11 in the pathogenesis of DPN. In this study, Rab11 expression decreased in the sciatic nerves of diabetic mice with impaired conduction function versus those of normal mice. In vitro experiment revealed interferon‐γ (IFN‐γ), not high glucose and interleukin 1β was the main factor to lead to Rab11 downregulation in RSC96 cells. Again, both Rab11 knockdown and IFN‐γ treatment caused cell viability inhibition and the decrease in BrdU‐positive cells. In contrast, overexpression of Rab11 reversed IFN‐γ‐reduced cell proliferation. Furthermore, mTORC1 not mTORC2 was proven to be suppressed by IFN‐γ treatment in RSC96 cells, indicated in decreased phospho‐p70S6K. Inhibition of the mTORC1 pathway resulted in Rab11 expression downregulation in RSC96 cells. Activation of the mTORC1 pathway effectively prevented IFN‐γ‐reduced Rab11 expression in RSC96 cells. Also, glucose transporter 1 (GLUT1) was found to be downregulated in RSC96 cells with Rab11 silence and overexpression of GLUT1 reversed Rab11 blocking‐caused proliferation inhibition. Taken together, our findings suggest that IFN‐γ decreases Rab11 expression via the inhibition of the mTORC1 signaling pathway, causing reduced cell proliferation in Schwann cells of DPN by GLUT1 downregulation.

Mechanism of Schwann cells in diabetic peripheral neuropathy: A review

“…Therefore, mTORC1/ www.md-journal.com Rab11/GLU transporter 1 cascade pathway is an effective way to improve the function of SCs and prevent the onset of DPN. [16] 1. 6…”