Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

Bernhart, Eva; Kollroser, Manfred; Rechberger, Gerald; Reicher, Helga; Heinemann, Ákos; Schratl, Petra; Hallström, Seth; Wintersperger, Andrea; Nusshold, Christoph; DeVaney, Trevor; Zorn-Pauly, Klaus; Malli, Roland; Graier, Wolfgang F.; Malle, Ernst; Sattler, Wolfgang

doi:10.1002/pmic.200900195

Cited by 70 publications

(61 citation statements)

References 66 publications

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“…Activated microglia can scavenge, present antigens, phagocytose, and release inflammatory mediators during injury and neurodegeneration (Hu et al, 2014). Microglia from mouse or rat mainly express Lpar1 and/or Lpar3 (Moller et al, 2001; Tham et al, 2003), while human microglial cell lines express LPAR1-3 (Moller et al, 2001; Bernhart et al, 2010). Receptor activation by LPA can induce intracellular calcium mobilization and potassium channel activation, as well as cell proliferation, cell morphology changes, upregulated chemokinesis, and membrane ruffling (Schilling et al, 2004; Fujita et al, 2008; Muessel et al, 2013).…”

Section: Lparsmentioning

confidence: 99%

Lysophosphatidic Acid Signaling in the Nervous System

Yung

Stoddard

Mirendil

et al. 2015

Neuron

219

177

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Summary The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.

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Section: Lparsmentioning

confidence: 99%

Lysophosphatidic Acid Signaling in the Nervous System

Yung

Stoddard

Mirendil

et al. 2015

Neuron

219

177

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“…RhoA/ROCK induces changes in the actin cytoskeleton necessary for cell motility, process retraction and cell spreading, which characterize activation of inflammatory cells, including microglia (Bernhart et al, 2010). Activation of the microglial RhoA/ROCK pathway plays a major role in the effect of Ang II/AT1/Nox axis on microglial polarization and neurodegeneration.…”

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

193

182

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Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

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“…Microglia can express a range of LP receptors including LPA 1 , LPA 2 , LPA 3 , S1P 1 , S1P 2 , S1P 3 , and S1P 5 [52,53,116–118]. LPA signaling was reported to regulate proliferation, membrane ruffling and hyperpolarization, metabolic changes, migration, chemokinesis, and growth factor upregulation [52,116,117,119,120]. S1P or its biosynthetic enzymes were reported to regulate membrane hyperpolarization and production of neurotoxic molecules such as tumor necrosis factor-α, interleukin-1β, and nitric oxide [53,116,121,122].…”

Section: Biological Functions Of Lpa and S1p Receptors In Cns Cellmentioning

confidence: 99%

Lysophospholipids and their receptors in the central nervous system

Choi

Chun

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

228

242

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Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA1–6 and S1P1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including Gi/o, G12/13, Gq and Gs, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

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Lysophosphatidic acid receptor activation affects the C13NJ microglia cell line proteome leading to alterations in glycolysis, motility, and cytoskeletal architecture

Cited by 70 publications

References 66 publications

Lysophosphatidic Acid Signaling in the Nervous System

Lysophosphatidic Acid Signaling in the Nervous System

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Lysophospholipids and their receptors in the central nervous system

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