Persistent Acidic Environment Induces Impaired Phagocytosis via ERK in Microglia

• Published in: Neurochemical research Vol. 47; no. 5; pp. 1341 - 1353
• Main Authors: Jang, Kyu-Beom, You, Min-Jung, Yang, Bohyun, Rim, Chan, Kim, Hui-Ju, Kwon, Min-Soo
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2022; Springer Nature B.V
• Subjects: Alzheimer's disease; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell death; Central nervous system; CX3CR1 protein; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Growth factors; Head injuries; Interleukin 10; Interleukin 6; Kinases; Lymphocytes; Lymphocytes T; Mice; Microglia; Microglia - metabolism; mRNA; Neonates; Neurochemistry; Neurodegenerative diseases; Neurological diseases; Neurology; Neurosciences; Original Paper; pH effects; Phagocytes; Phagocytosis; Protein kinase A; Traumatic brain injury; Phagocytosis; Neurological disorders; Acidic environment; Cytokine; Microglia; ERK
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-022-03533-z

Acidic environment evoked by stroke, traumatic brain injury, and Alzheimer’s disease may change the functional properties of microglia. Nevertheless, the underlying mechanisms of functional changes in microglia remain unclear. In this study, we found that acidic stimuli (pH 6.8) increased rapidly interleukin (IL)-1β and IL-6 mRNA levels and subsequently reduced IL-10 , transforming growth factor (TGF)-β1, Cx3cr1 , and P2ry12 as the exposure time to acidic environment increase in BV2 cells. In addition, persistent acidic environment (pH 6.8 for 6 h) induced impaired phagocytic function in BV2 cells. Short-term acidic exposure (pH 6.8 for 30 min) increased cyclic AMP (cAMP) and phospho-protein kinase A (PKA) but inhibited phospho-extracellular signal-regulated kinase (p-ERK). However, under persistent acidic environment (pH 6.8 for 6 h), cyclic AMP and PKA were normalized and p-ERK was increased with TDAG8 (T cell death associated gene 8; GPR65) reduction. FR 180,204, an ERK inhibitor, rescued the persistent acidic environment-induced functional changes in BV2 cells and its effect was recapitulated in primary neonatal microglia. Thus, we propose that ERK targeting may be an alternative strategy to restore microglial dysfunction in the central nervous system (CNS) acidic environment in various neurological disorders.