Research Paper Volume 11, Issue 2 pp 697—706
Chronic hyperglycemia regulates microglia polarization through ERK5
- 1 Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 2 Reproductive Medicine Centre, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 3 Department of Pediatric Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 4 Department of Pediatric Endocrinology and Metabolism, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China
- 5 Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA
received: December 7, 2018 ; accepted: January 7, 2019 ; published: January 26, 2019 ;https://doi.org/10.18632/aging.101770
How to Cite
Copyright: Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Diabetic patients are prone to developing Alzheimer’s disease (AD), in which microglia play a critical role. However, the direct effect of high glucose (HG) on microglia and the role of extracellular-signal-regulated kinase 5 (ERK5) signaling in this interaction have not been examined before. Here, these questions were addressed in microglia cultured in HG versus normal glucose (NG) conditions. Initially, HG induced microglial differentiation into the M2a phenotype with concomitant ERK5 activation. However, longer exposure to HG further induced differentiation of microglia into the M2b-like phenotype, followed by the M1-like subtype, concomitant with a gradual loss of ERK5 activation. BIX021895, a specific inhibitor of ERK5 activation, prevented M2a- differentiation of microglia, but induced earlier M2b-like polarization followed by M1-like polarization. Transfection of microglia with a sustained activated form of MEK5 (MEK5DD) prolonged the duration of the M2a phenotype, and prevented later differentiation into the M2b/M1 subtype. Conditioned media from the M2a-polarized microglia reduced neuronal cell apoptosis in hypoxic condition, while media from M2b-like or M1-like microglia enhanced apoptosis. Together, our data suggest that chronic hyperglycemia may induce a gradual alteration of microglia polarization into an increasingly proinflammatory subtype, which could be suppressed by sustained activation of ERK5 signaling.