2. Academic Validation
  3. RAGE activation in macrophages and development of experimental diabetic polyneuropathy

RAGE activation in macrophages and development of experimental diabetic polyneuropathy

  • JCI Insight. 2022 Dec 8;7(23):e160555. doi: 10.1172/jci.insight.160555.
Sho Osonoi 1 2,  Hiroki Mizukami 1,  Yuki Takeuchi 1 2,  Hikari Sugawa 3,  Saori Ogasawara 1,  Shizuka Takaku 4,  Takanori Sasaki 1,  Kazuhiro Kudoh 1,  Koichi Ito 5,  Kazunori Sango 4,  Ryoji Nagai 3,  Yasuhiko Yamamoto 6,  Makoto Daimon 2,  Hiroshi Yamamoto 7,  Soroku Yagihashi 1
Affiliations

Affiliations

  • 1 Department of Pathology and Molecular Medicine and.
  • 2 Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
  • 3 Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, Higashi-ku, Kumamoto, Japan.
  • 4 Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
  • 5 Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan.
  • 6 Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
  • 7 Komatsu University, Komatsu, Japan.
PMID: 36477360 DOI: 10.1172/jci.insight.160555
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.

Keywords

Diabetes; Endocrinology; Neurodegeneration; Neuroendocrine regulation; Neuroscience.

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