β-Arrestins 1 and 2 differentially regulate LPS-induced signaling and pro-inflammatory gene expression

Fan, Hongkuan; Luttrell, Louis M.; Tempel, G; Senn, Joseph J.; Halushka, Perry V.; Cook, James A.

doi:10.1016/j.molimm.2007.02.009

Cited by 77 publications

(72 citation statements)

References 46 publications

(48 reference statements)

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“…NMDA activation-induced dendrite spine remodeling in neurons is dependent on the scaffolding protein ␤-arrestin-2 (24). This was of interest because ␤-arrestin-2 is known to modulate LPS-induced inflammatory responses, but its role in inflammasome activation is not known (5,22,25,33). Our results clearly show that aspartate-dependent downregulation of inflammasome function in vitro and in vivo is dependent on ␤-arrestin-2.…”

Section: G735mentioning

confidence: 60%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Farooq A, Hoque R, Ouyang X, Farooq A, Ghani A, Ahsan K, Guerra M, Mehal WZ. Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a ␤-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol 307: G732-G740, 2014. First published August 7, 2014; doi:10.1152/ajpgi.00073.2014.-Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a ␤-arrestin-2 NF-k␤ and JNK pathway and not via Ca 2ϩ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.aspartate

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Section: G735mentioning

confidence: 60%

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Farooq

Hoque

Ouyang

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…31,32 Interestingly, the expression level of b-arrestin2 was found to be decreased as a result of TLRs activation, through transcriptional and translational mechanisms, 33 and in mouse embryonic fibroblast cells b-arrestin2 has been reported to negatively regulate TLR4-mediated NF-kB activation. 34 To investigate the potential involvement of b-arrestin signaling in KOR-mediated anti-inflammation in microglia, we first checked the expression level of b-arrestin proteins in BV2 cells at different time points Figure 3a shows a robust increase in b-arrestin2 protein levels as soon as 10 min following Dyn treatment, whereas b-arrestin1 remained the same before and after Dyn treatment. Meanwhile, b-arrestin2 mRNA levels showed no significant increase after Dyn treatment (Supplementary Figure S4).…”

Section: Resultsmentioning

confidence: 99%

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Feng

Burton

et al. 2013

Cell Death Differ

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Microglial activation worsens neuronal loss and contributes to progressive neurological diseases like Parkinson's disease (PD). This inflammatory progression is countered by dynorphin (Dyn), the endogenous ligand of the kappa-opioid receptor (KOR). We show that microglial b-arrestin mediates the ability of Dyn/KOR to limit endotoxin-elicited production of pro-inflammatory effectors and cytokines, subsequently protecting neurons from inflammation-induced neurotoxicity. Agonist-activated KOR enhances the interaction of b-arrestin2 with transforming growth factor-beta-activated kinase 1 (TAK1)-binding protein 1 (TAB1), disrupting TAK1-TAB1 mediated pro-inflammatory gene expression. We reveal a new physiological role for b-arrestin in neuroprotection via receptor internalization-triggered blockade of signal effectors of microglial inflammatory neurotoxicity. This result offers novel drug targets in the convergent KOR/b-arrestin2 and inflammatory pathways for treating microglial inflammatory neuropathologies like PD. Cell Death and Differentiation (2014) 21, 397-406; doi:10.1038/cdd.2013 published online 25 October 2013 Increasing evidence suggests that the overactivation of immune system-derived microglia in the substantia nigra (SN) is a key causative factor in the pathogenesis of Parkinson's disease (PD), the most prevalent neurodegenerative disease in the population over 60 years old. Pathologically, PD is characterized by the degeneration of dopaminergic (DA) neurons of the SN pars compacta (SNpc) in the midbrain, leading to disabled voluntary movements. Immunohistochemistry research has indicated that activated microglia accumulate around degenerating neurons in the SN of patients with PD and related parkinsonian syndromes. 1 Although microglial activation in these diseases is not limited to the SN, the DA neurons in the SN are particularly vulnerable to inflammatory insult owing to the larger population of microglia in the SN. 2,3 As a sensor of brain injury and aging, microglia's state and activity are regulated through neuronmicroglia communication involving the stimulation of signal transducing or phagocytic microglial receptors by neurotransmitters. 4,5 Deficiencies in this communication between neurons and microglia as a result of stress or aging leads to reactive microglia and prolonged inflammation and, as a result, neuronal death. Similarly, stimulation of microglia by bacteria or endotoxins results in outbursts of pro-inflammatory cytokines such as interleukin 1 beta (IL-1b), tumor necrosis factor-a (TNF)-a, and interleukin 6 (IL-6) through activation of toll-like receptor 4 (TLR4). This can contribute to the death of neurons in the SN because long-term inhibition of IL-1b and TNF-a has consistently been reported to attenuate tyrosine hydroxylase (TH þ ) neuron loss in PD models. 6,7 Meanwhile, neuron degeneration itself leads to further secondary activation of microglia via increased production of matrix metalloproteinase 3 and neuromelaine and, as a result, further neuronal death. [8][9][10] Thus...

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“…Although knockdown of ␤ARR1 and ␤ARR2 was required to inhibit resensitization and internalization-dependent nuclear ERK signaling, ␤ARR2 siRNA alone attenuated SPstimulated activation of NF-B and IL-8 release, suggesting that ␤ARR2 promotes SP inflammatory signaling in colonocytes. ␤ARR2 also mediates lipopolysaccharide-stimulated IL-8 secretion (30). One explanation for the proinflammatory action of ␤ARR2 could be the ␤ARR2-dependent recruitment of regulators of NF-B activation to the NK 1 R. Similarly, ␤ARR2 recruits CARMA3 to the lysophosphatidic acid receptor to stimulate NF-B activation (31).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

Jensen¹,

Halls²,

Murphy

et al. 2014

Journal of Biological Chemistry

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Background: Agonists stimulate the subcellular redistribution of receptors. The importance of trafficking for pathophysiological processes is unknown. Results: Substance P inflammatory signaling required receptor interaction with ␤-arrestins and endothelin-converting enzyme, which mediated endocytosis and recycling. Conclusion: Sustained substance P inflammatory signaling requires receptor recycling. Significance: Mechanisms that maintain receptors at the cell surface are necessary for sustained signaling by extracellular agonists.

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β-Arrestins 1 and 2 differentially regulate LPS-induced signaling and pro-inflammatory gene expression

Cited by 77 publications

References 46 publications

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway

β-arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Endothelin-converting Enzyme 1 and β-Arrestins Exert Spatiotemporal Control of Substance P-induced Inflammatory Signals

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