Signaling Pathways Controlling Microglia Chemotaxis

Yang, Fan; Xie, Lirui; Chung, Chang Y.

doi:10.14348/molcells.2017.0011

Cited by 86 publications

(57 citation statements)

References 48 publications

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“…The DA-induced increase in cell spreading was also recapitulated in resting BV 2 microglia cells ( Figure 1B ). Recent evidences indicated that microglia exhibit two functionally different activation states that are referred to as classical (pro-inflammatory, M1) and alternative activation (anti-inflammatory, M2) ( Yang et al, 2017 ). Microglia exposed to LPS, a common stimulus that triggers a pro-inflammatory phenotype (M1 activated microglia) exhibited increased expression of IL-6 and iNOS, amoeboid morphology, and increased phagocytic activity ( Figures 1C , 3C ).…”

Section: Resultsmentioning

confidence: 99%

Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine

Yang

Chen

Pathak

et al. 2018

Front. Cell. Neurosci.

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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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Section: Resultsmentioning

confidence: 99%

Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine

Yang

Chen

Pathak

et al. 2018

Front. Cell. Neurosci.

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“…Our results demonstrate that exogenous LPA induced activation of the PKD, MAPK, and AKT pathways, as well as phosphorylation of NF-κB, STAT1, STAT3, and c-Jun in a CRT0066101-sensitive manner both in BV-2 and PMM. All of these signaling pathways were reported to be involved in microglial polarization [ 77 ] and chemotaxis [ 78 ]. These findings indicate a sensor function for LPAR5 that transmits intracellular signals via PKD isoforms.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype

Plastira

Bernhart

Goeritzer

et al. 2017

J Neuroinflammation

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BackgroundExtracellular lysophosphatidic acid (LPA) species transmit signals via six different G protein-coupled receptors (LPAR1–6) and are indispensible for brain development and function of the nervous system. However, under neuroinflammatory conditions or brain damage, LPA levels increase, thereby inducing signaling cascades that counteract brain function. We describe a critical role for 1-oleyl-2-hydroxy-sn-glycero-3-phosphate (termed “LPA” throughout our study) in mediating a motile and pro-inflammatory microglial phenotype via LPAR5 that couples to protein kinase D (PKD)-mediated pathways.MethodsUsing the xCELLigence system and time-lapse microscopy, we investigated the migrational response of microglial cells. Different M1 and M2 markers were analyzed by confocal microscopy, flow cytometry, and immunoblotting. Using qPCR and ELISA, we studied the expression of migratory genes and quantitated the secretion of pro-inflammatory cytokines and chemokines, respectively. Different transcription factors that promote the regulation of pro-inflammatory genes were analyzed by western blot. Reactive oxygen species (ROS) and nitric oxide (NO) production, phagocytosis, and microglial cytotoxicity were determined using commercially available assay kits.ResultsLPA induces MAPK family and AKT activation and pro-inflammatory transcription factors’ phosphorylation (NF-κB, c-Jun, STAT1, and STAT3) that were inhibited by both LPAR5 and PKD family antagonists. LPA increases migratory capacity, induces secretion of pro-inflammatory cytokines and chemokines and expression of M1 markers, enhances production of ROS and NO by microglia, and augments cytotoxicity of microglial cell-conditioned medium towards neurons. The PKD family inhibitor blunted all of these effects. We propose that interference with this signaling axis could aid in the development of new therapeutic approaches to control neuroinflammation under conditions of overshooting LPA production.ConclusionsIn the present study, we show that inflammatory LPA levels increased the migratory response of microglia and promoted a pro-inflammatory phenotype via the LPAR5/PKD axis. Interference with this signaling axis reduced microglial migration, blunted microglial cytotoxicity, and abrogated the expression and secretion of pro-inflammatory mediators.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1024-1) contains supplementary material, which is available to authorized users.

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“…The signaling pathways involved in microglia chemotaxis are highly complex. Briefly, studies have highlighted the specific roles of extracellular signal–regulated kinases (ERK1/2), protein kinase A (PKA), phospholipase A2 (PLA2), phosphoinositide 3-kinase (PI3K), and ATP/purinergic receptor signaling pathways in regulating microglial migration (Fan et al, 2017 ). Monocyte chemoattractant proteins (MCPs) are of particular interest in neuroinflammatory conditions.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

2017

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Brain aging is central to late-onset Alzheimer's disease (LOAD), although the mechanisms by which it occurs at protein or cellular levels are not fully understood. Alzheimer's disease is the most common proteopathy and is characterized by two unique pathologies: senile plaques and neurofibrillary tangles, the former accumulating earlier than the latter. Aging alters the proteostasis of amyloid-β peptides and microtubule-associated protein tau, which are regulated in both autonomous and non-autonomous manners. Microglia, the resident phagocytes of the central nervous system, play a major role in the non-autonomous clearance of protein aggregates. Their function is significantly altered by aging and neurodegeneration. This is genetically supported by the association of microglia-specific genes, TREM2 and CD33, and late onset Alzheimer's disease. Here, we propose that the functional characterization of microglia, and their contribution to proteopathy, will lead to a new therapeutic direction in Alzheimer's disease research.

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Signaling Pathways Controlling Microglia Chemotaxis

Cited by 86 publications

References 48 publications

Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine

Differential Regulation of Adhesion and Phagocytosis of Resting and Activated Microglia by Dopamine

Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype

Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy

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