β-Arrestins 1 and 2 are critical regulators of inflammation

Fan, Hongkuan

doi:10.1177/1753425913501098

Cited by 30 publications

(21 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since then, several pieces of evidence, when taken together, suggest that β 2 AR-mediated β-arrestin-dependent signaling is pro-inflammatory in asthma. Firstly, β-arrestins have been implicated as regulators of inflammation in a variety of diseases including asthma, sepsis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and atherosclerosis [24,25]. Lung β-arrestin expression is up-regulated in murine models of asthma [10] and is similarly dynamically regulated in other inflammatory diseases [24].…”

Section: β2ar and Par2 Signaling In Asthmamentioning

confidence: 99%

“…Firstly, β-arrestins have been implicated as regulators of inflammation in a variety of diseases including asthma, sepsis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and atherosclerosis [24,25]. Lung β-arrestin expression is up-regulated in murine models of asthma [10] and is similarly dynamically regulated in other inflammatory diseases [24]. Results from multiple murine studies have shown that the asthma phenotype is strikingly diminished in β-arrestin-2 −/− mice irrespective of the method of induction of allergic airway disease [4,12,19].…”

Section: β2ar and Par2 Signaling In Asthmamentioning

confidence: 99%

See 1 more Smart Citation

Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Walker¹,

DeFea²

2014

Current Opinion in Pharmacology

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) utilize (at least) two signal transduction pathways to elicit cellular responses including the classic G protein-dependent, and the more recently discovered β-arrestin-dependent, signaling pathways. In human and murine models of asthma, agonist-activation of β2-adrenergic receptor (β2AR) or Protease-activated-receptor-2 (PAR2) results in relief from bronchospasm via airway smooth muscle relaxation. However, chronic activation of these receptors, leads to pro-inflammatory responses. One plausible explanation underlying the paradoxical effects of β2AR and PAR2 agonism in asthma is that the beneficial and harmful effects are associated with distinct signaling pathways. Specifically, G protein-dependent signaling mediates relaxation of airway smooth muscle, whereas β-arrestin-dependent signaling promotes inflammation. This review explores the evidence supporting the hypothesis that β-arrestin-dependent signaling downstream of β2AR and PAR2 is detrimental in asthma and examines the therapeutic opportunities for selectively targeting this pathway.

show abstract

Section: β2ar and Par2 Signaling In Asthmamentioning

confidence: 99%

Section: β2ar and Par2 Signaling In Asthmamentioning

confidence: 99%

Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Walker¹,

DeFea²

2014

Current Opinion in Pharmacology

View full text Add to dashboard Cite

show abstract

“…5 However, there is still a limited understanding about the regulatory mechanism of NOD2 on the inflammation of cerebral I/R. 9 Li et al reported ARRB2 acts 6 More recently, β-arrestins have been identified as scaffold proteins binding with various target molecules and thus regulating a wide range of biological processes.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 Growing evidence shows that β-arrestin 2 (ARRB2) play a critical regulatory role in the inflammatory response. 9 Li et al reported ARRB2 acts…”

Section: Introductionmentioning

confidence: 99%

β‐arrestin 2 negatively regulates NOD2 signalling pathway through association with TRAF6 in microglia after cerebral ischaemia/reperfusion injury

Chen

Kong

Wei

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

We previously reported that nucleotide‐binding oligomerization domain‐containing protein ( NOD ) 2 was involved in the inflammatory responses to cerebral ischaemia/reperfusion (I/R) insult. However, the mechanism by which NOD 2 participates in brain ischaemic injury and the regulation of NOD 2 in the process are still obscure. Increased β‐arrestin 2 ( ARRB 2) expression was observed in microglia following cerebral I/R in wild‐type mice besides the up‐regulation of NOD 2 and TRAF 6. Stimulation of NOD 2 by muramyl dipeptide ( MDP ) in BV 2 cells induced the activation of NF ‐κB by the phosphorylation of p65 subunit and the degradation of IκBα. Meanwhile, the protein level of Cyclooxygenase‐2 (COX‐2), the protein expression and activity of MMP ‐9 were significantly increased in BV 2 cells after administration of MDP . Furthermore, overexpression of ARRB 2 significantly suppressed the inflammation induced by MDP , silence of ARRB 2 significantly enhanced the inflammation induced by MDP in BV 2 cells. In addition, we observed endogenous interaction of TRAF 6 and ARRB 2 after stimulation of MDP or cerebral I/R insult, indicating ARRB 2 negatively regulates NOD 2‐triggered inflammatory signalling pathway by associating with TRAF 6 in microglia after cerebral I/R injury. Finally, the in vivo study clearly confirmed that ARRB 2 negatively regulated NOD 2‐induced inflammatory response, as ARRB 2 deficiency exacerbated stroke outcomes and aggravated the NF ‐κB signalling pathway induced by NOD 2 stimulation after cerebral I/R injury. These findings revealed ARRB 2 negatively regulated NOD 2 signalling pathway through the association with TRAF 6 in cerebral I/R injury.

show abstract

“…It is worth noting that ARRB1 and ARRB2 competitively interact with p65 and the interaction is completely dependent on in ammatory stimulation, suggestive of p65 activation-dependent interaction. Previous studies have revealed that the effects of ARRBs on the activation of the NF-κB pathway depend on stimuli and cell types studied [28,59] and the underlying mechanisms may involve direct interaction with IκBα, IKKα, and ΙΚΚβ [49][50][51]. Our data not only suggest a novel mechanism by which ARRBs activate the NF-κB pathway, but also imply distinct functions of ARRBs in PD being attributable to their different abilities to interact with p65.…”

Section: Discussionmentioning

confidence: 54%

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Fang

Jiang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Although β-arrestins (ARRBs) regulate diverse physiological and pathophysiological processes, their function and regulation in Parkinson’s disease (PD) remain poorly defined. Methods We measured expression of ARRB1 and ARRB2 in liposaccharide (LPS)-induced and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. ARRB1-deficient and ARRB2-deficient mouse were used to assess the impact of ARRBs on dopaminergic (DA) neuron loss and microglia activation in PD mouse models. After primary mouse DA neurons were exposed to the conditioned medium from ARRB1 knockdown or ARRB2 knockout microglia stimulated by LPS plus interferon γ (IFN-γ), the degeneration of DA neurons was quantified. Gain- and loss-of-function studies were used to study the effects of ARRBs on microglia activation in vitro. To further understand the mechanism, we measured the activation of classical inflammatory pathways and used RNA sequencing to identify the novel downstream effector of ARRBs. Result In this study, we demonstrate that expression of ARRB1 and ARRB2, particularly in microglia, is reciprocally regulated in PD mouse models. ARRB1 ablation ameliorates, whereas ARRB2 knockout aggravates, the pathological features of PD, including DA neuron loss, neuroinflammation and microglia activation in vivo, as well as microglia-mediated neuron damage and inflammation in vitro. In parallel, ARRB1 and ARRB2 produce adverse effects on the activation of inflammatory signal transducers and activators of transcription 1 (STAT1) and nuclear factor-κB (NF-κB) pathways in microglia. We also show that two ARRBs competitively interact with activated p65 in the NF-κB pathway and that nitrogen permease regulator-like 3 (Nprl3), a functionally poorly characterized protein, is a novel effector acting downstream of both ARRBs. Conclusion Collectively, these data demonstrate that two closely related ARRBs have completely opposite functions in microglia-mediated inflammatory responses, via Nprl3, and differentially affect the pathogenesis of PD, and suggest a potential therapeutic strategy.

show abstract

β-Arrestins 1 and 2 are critical regulators of inflammation

Cited by 30 publications

References 80 publications

Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

β‐arrestin 2 negatively regulates NOD2 signalling pathway through association with TRAF6 in microglia after cerebral ischaemia/reperfusion injury

Opposing functions of β-arrestin 1 and 2 in Parkinson’s disease via microglia inflammation and Nprl3

Contact Info

Product

Resources

About