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. 2021 Apr;69(4):971-996.
doi: 10.1002/glia.23942. Epub 2020 Nov 29.

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin-2 and pyruvate dehydrogenase kinase-2 axis in the dorsal root ganglion

Anup Bhusal  1   2 , Md Habibur Rahman  1   2   3 , Won-Ha Lee  4 , In-Kyu Lee  5   6 , Kyoungho Suk  1   2   3
Affiliations

Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin-2 and pyruvate dehydrogenase kinase-2 axis in the dorsal root ganglion

Anup Bhusal et al. Glia. 2021 Apr.

Abstract

Diabetic peripheral neuropathy (DPN) is a common complication of uncontrolled diabetes. The pathogenesis of DPN is associated with chronic inflammation in dorsal root ganglion (DRG), eventually causing structural and functional changes. Studies on DPN have primarily focused on neuronal component, and there is limited knowledge about the role of satellite glial cells (SGCs), although they completely enclose neuronal soma in DRG. Lipocalin-2 (LCN2) is a pro-inflammatory acute-phase protein found in high levels in diverse neuroinflammatory and metabolic disorders. In diabetic DRG, the expression of LCN2 was increased exclusively in the SGCs. This upregulation of LCN2 in SGCs correlated with increased inflammatory responses in DRG and sciatic nerve. Furthermore, diabetes-induced inflammation and morphological changes in DRG, as well as sciatic nerve, were attenuated in Lcn2 knockout (KO) mice. Lcn2 gene ablation also ameliorated neuropathy phenotype as determined by nerve conduction velocity and intraepidermal nerve fiber density. Mechanistically, studies using specific gene KO mice, adenovirus-mediated gene overexpression strategy, and primary cultures of DRG SGCs and neurons have demonstrated that LCN2 enhances the expression of mitochondrial gate-keeping regulator pyruvate dehydrogenase kinase-2 (PDK2) through PPARβ/δ, thereby inhibiting pyruvate dehydrogenase activity and increasing production of glycolytic end product lactic acid in DRG SGCs and neurons of diabetic mice. Collectively, our findings reveal a crucial role of glial LCN2-PPARβ/δ-PDK2-lactic acid axis in progression of DPN. Our results establish a link between pro-inflammatory LCN2 and glycolytic PDK2 in DRG SGCs and neurons and propose a novel glia-based mechanism and drug target for therapy of DPN. MAIN POINTS: Diabetes upregulates LCN2 in satellite glia, which in turn increases pyruvate dehydrogenase kinase-2 (PDK2) expression and lactic acid production in dorsal root ganglia (DRG). Glial LCN2-PDK2-lactic acid axis in DRG plays a crucial role in the pathogenesis of diabetic neuropathy.

Keywords: diabetes; dorsal root ganglion; lipocalin-2; neuropathy; pyruvate dehydrogenase kinase; satellite glial cells.

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References

REFERENCES

    1. Abdollahi, M., Ng, T. S., Rezaeizadeh, A., Aamidor, S., Twigg, S. M., Min, D., & McLennan, S. V. (2017). Insulin treatment prevents wounding associated changes in tissue and circulating neutrophil MMP-9 and NGAL in diabetic rats. PLoS One, 12(2), e0170951. https://doi.org/10.1371/journal.pone.0170951
    1. Abella, V., Scotece, M., Conde, J., Gomez, R., Lois, A., Pino, J., … Gualillo, O. (2015). The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers, 20(8), 565-571. https://doi.org/10.3109/1354750X.2015.1123354
    1. Al Nimer, F., Elliott, C., Bergman, J., Khademi, M., Dring, A. M., Aeinehband, S., … Piehl, F. (2016). Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination. Neurol. Neuroimmunol. Neuroinflamm., 3(1), e191. https://doi.org/10.1212/NXI.0000000000000191
    1. Andersson, A. K., Ronnback, L., & Hansson, E. (2005). Lactate induces tumour necrosis factor-alpha, interleukin-6 and interleukin-1beta release in microglial- and astroglial-enriched primary cultures. Journal of Neurochemistry, 93(5), 1327-1333. https://doi.org/10.1111/j.1471-4159.2005.03132.x
    1. Arellano-Buendia, A. S., Garcia-Arroyo, F. E., Cristobal-Garcia, M., Loredo-Mendoza, M. L., Tapia-Rodriguez, E., Sanchez-Lozada, L. G., & Osorio-Alonso, H. (2014). Urinary excretion of neutrophil gelatinase-associated lipocalin in diabetic rats. Oxidative Medicine and Cellular Longevity, 2014, 961326. https://doi.org/10.1155/2014/961326

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