Browsing by Author "Fan, Yang"

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    Differential regulation of adhesion and phagocytosis of resting and activated microglia by dopamine
    (Frontiers in Cellular Neuroscience, 2018-09-11) Fan, Yang; Chen, Zhilu; Pathak, Janak L; Carneiro, Ana MD; Chung, Chang Y
    © 2018 Fan, Chen, Pathak, Carneiro and Chung. Microglia, the immune competent cells of the central nervous system (CNS), normally exist in a resting state characterized by a ramified morphology with many processes, and become activated to amoeboid morphology in response to brain injury, infection, and a variety of neuroinflammatory stimuli. Many studies focused on how neurotransmitters affect microglia activation in pathophysiological circumstances. In this study, we tried to gain mechanistic insights on how dopamine (DA) released from neurons modulates cellular functions of resting and activated microglia. DA induced the reduction of the number of cellular processes, the increase of cell adhesion/spreading, and the increase of vimentin filaments in resting primary and BV2 microglia. In contrast to resting cells, DA downregulated the cell spreading and phagocytosis of microglia activated by LPS. DA also significantly downregulated ERK1/2 phosphorylation in activated microglia, but not in resting microglia. Downregulation of ERK1/2 by DA in activated microglia required receptor signaling. In contrast, we found a significant increase of p38MAPK activity by DA treatment in resting, but not in activated microglia. These latter effects required the uptake of DA through the high-affinity transporter but did not require receptor signaling. Activation of p38MAPK resulted in the increase of focal adhesion number via phosphorylation of paxillin at Ser83. These results indicate that DA might have a differential, depending upon the activation stage of microglia, impact on cellular functions such as adhesion and phagocytosis.
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    Mefenamic acid can attenuate depressive symptoms by suppressing microglia activation induced upon chronic stress.
    (Brain research, 2020-08) Feng, Xiaoye; Fan, Yang; Chung, Chang Y
    BACKGROUND:Depression is the most debilitating neuropsychiatric disorder, and psychosocial stressors are major risk factors for the onset of depression. Depression is closely associated with chronic inflammation and microglia are the principal mediators of inflammation in the central nervous system (CNS). Mefenamic acid (MA) and celecoxib are nonselective and selective inhibitors of cyclooxygenase (COX), respectively. COX is a key enzyme in mediating inflammatory response in microglia. In this study, we examine the effects of inhibiting COX by MA on depressive-like behaviors and microglia activation in the hippocampus. METHODS:We evaluate the effect of MA on chronic mild stress (CMS) induced depressive-like behavior by sucrose preference and forced swimming tests. Effect of MA on microglia activation in dentate gyrus (DG) of hippocampus was examined by immunohistochemistry. In vitro experiments including western blotting and phagocytosis assay were used to investigate the effect of MA on microglia activation. RESULTS:Behavioral assays reveal MA and celecoxib ameliorate CMS-induced depressive-like behavior. Compared to the stressed mice, the number of activated/phagocytic microglia (Iba1+/CD68+) in DG of hippocampus significantly decreases in stressed mice treated with MA or celecoxib. MA and celecoxib play a role in inhibiting microglia activation by inhibiting of ERK1/2 and P38 MAPK activation and iNOS expression. MA or celecoxib also reduce the high phagocytic activity of activated microglia. CONCLUSION:MA inhibits microglia activation/phagocytosis induced upon chronic stress in the hippocampus, which might result in the improvement of depressive symptoms.
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    Signaling Pathways Controlling Microglia Chemotaxis.
    (Molecules and cells, 2017-03-17) Fan, Yang; Xie, Lirui; Chung, Chang Y
    Microglia are the primary resident immune cells of the central nervous system (CNS). They are the first line of defense of the brain's innate immune response against infection, injury, and diseases. Microglia respond to extracellular signals and engulf unwanted neuronal debris by phagocytosis, thereby maintaining normal cellular homeostasis in the CNS. Pathological stimuli such as neuronal injury induce transformation and activation of resting microglia with ramified morphology into a motile amoeboid form and activated microglia chemotax toward lesion site. This review outlines the current research on microglial activation and chemotaxis.