Alcohol-Induced Interactive Phosphorylation of Src and Toll-like Receptor Regulates the Secretion of Inflammatory Mediators by Human Astrocytes

Floreani, Nicholas A.; Rump, Travis J.; Muneer, P. M. Abdul; Alikunju, Saleena; Morsey, Brenda; Brodie, Michael R.; Persidsky, Yuri; Haorah, James

doi:10.1007/s11481-010-9213-z

Cited by 51 publications

(39 citation statements)

References 43 publications

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“…Activation of TLR4 causes hyperalgesia (Calil et al, 2014; Watkins et al, 2009). Importantly, alcohol exposure can increase TLR4 expression and TLR4-facilitated secretion of pro-inflammatory mediators (Corrigan and Hutchinson, 2012; Floreani et al, 2010). One study has shown that the activation of DORs through mechanisms involving β-arrestin2 inhibit TLR4-induced release of tumor necrosis factor induced by the TLR4 agonist lipopolysaccharide in mast cells (Madera-Salcedo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Alongkronrusmee

Chiang

Rijn

2016

Drug and Alcohol Dependence

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Background As a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. Methods To study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. Results We created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3 g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. Conclusions DORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.

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Section: Discussionmentioning

confidence: 99%

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Alongkronrusmee

Chiang

Rijn

2016

Drug and Alcohol Dependence

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“…IL-1 and TLR4 signaling is important in these processes as demonstrated by the fact that neutralizing antibodies to IL-1R and TLR4 can suppress ethanol induction of these proinflammatory molecules and signaling pathways (Blanco et al, 2005). TLR4 was also shown to be critical in ethanol induction of Cox-2 and Src phosphorylation in astrocytes (Floreani et al, 2010). These observations suggest that ethanol induction of immune responses in the CNS occurs through the movement of these receptors to lipid rafts, resulting in the activation of signaling pathways that ultimately lead to the production of proinflammatory molecules.…”

Section: Link Between Ethanol and Immune Responsesmentioning

confidence: 99%

Fetal Alcohol Spectrum Disorders and Neuroimmune Changes

Drew

Kane

2014

International Review of Neurobiology

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The behavioral consequences of fetal alcohol spectrum disorders (FASD) are serious and persist throughout life. The causative mechanisms underlying FASD are poorly understood. However, much has been learned about FASD from human structural and functional studies as well as from animal models, which have provided a greater understanding of the mechanisms underlying FASD. Using animal models of FASD, it has been recently discovered that ethanol induces neuroimmune activation in the developing brain. The resulting microglial activation, production of proinflammatory molecules, and alteration in expression of developmental genes are postulated to alter neuron survival and function and lead to long-term neuropathological and cognitive defects. It has also been discovered that microglial loss occurs, reducing microglia’s ability to protect neurons and contribute to neuronal development. This is important, because emerging evidence demonstrates that microglial depletion during brain development leads to long-term neuropathological and cognitive defects. Interestingly, the behavioral consequences of microglial depletion and neuroimmune activation in the fetal brain are particularly relevant to FASD. This chapter reviews the neuropathological and behavioral abnormalities of FASD and delineates correlates in animal models. This serves as a foundation to discuss the role of the neuroimmune system in normal brain development, the consequences of microglial depletion and neuroinflammation, the evidence of ethanol induction of neuroinflammatory processes in animal models of FASD, and the development of anti-inflammatory therapies as a new strategy for prevention or treatment of FASD. Together, this knowledge provides a framework for discussion and further investigation of the role of neuroimmune processes in FASD.

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“…Other agents such as lipopolysaccharides (LPS) can stimulate cPLA2 and PGE2 production through an ERK1/2-dependent pathway in astrocytes [58]. In fact, a number of other stimuli, including ammonia [59], alcohol [60], ceramide [61], bradykinin [62, 63], and diethylmaleate/iodoacetate [64] have been shown stimulate cPLA 2 and engage in astrocytic inflammatory and oxidative pathways.…”

Section: Cpla2 In Oxidative and Inflammatory Signaling Pathways In Asmentioning

confidence: 99%

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

et al. 2014

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Phospholipases A2 (PLA2s) are important enzymes for metabolism of fatty acids in membrane phospholipids. Among the three major classes of PLA2s in the mammalian system, the group IV calcium-dependent cytosolic PLA2 alpha (cPLA2α) has received the most attention because it is widely expressed in nearly all mammalian cells and its active participation in cell metabolism. Besides Ca2+ binding to its C-2 domain, this enzyme can undergo a number of cell-specific post-translational modifications, including phosphorylation by protein kinases, S-nitrosylation through interaction with nitric oxide (NO), as well as interaction with other proteins and lipid molecules. Hydrolysis of phospholipids by cPLA2 yields two important lipid mediators, arachidonic acid (AA) and lysophospholipids. While AA is known to serve as a substrate for cyclooxygenases and lipoxygenases, which are enzymes for synthesis of eicosanoids and leukotrienes, lysophospholipids are known to possess detergent-like properties capable of altering micro-domains of cell membranes. An important feature of cPLA2 is its link to cell surface receptors that stimulate signaling pathways associated with activation of protein kinases and production of reactive oxygen species (ROS). In the central nervous system (CNS), cPLA2 activation has been implicated in neuronal excitation, synaptic secretion, apoptosis, cell-cell interaction, cognitive and behavioral function, oxidative-nitrosative stress and inflammatory responses that underline the pathogenesis of a number of neurodegenerative diseases. However, the types of extracellular agonists that target intracellular signaling pathways leading to cPLA2 activation among different cell types and under different physiological and pathological conditions have not been investigated in detail. In this review, special emphasis is given to metabolic events linking cPLA2 to activation in neurons, astrocytes, microglial cells, and cerebrovascular cells. Understanding the molecular mechanism(s) for regulation of this enzyme is deemed important in the development of new therapeutic targets for treatment and prevention of neurodegenerative diseases.

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Alcohol-Induced Interactive Phosphorylation of Src and Toll-like Receptor Regulates the Secretion of Inflammatory Mediators by Human Astrocytes

Cited by 51 publications

References 43 publications

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

Fetal Alcohol Spectrum Disorders and Neuroimmune Changes

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

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