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

Abstract

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...

Adrenergic Receptors as Pharmacological Targets for Neuroinflammation and Neurodegeneration in Parkinson’s Disease

“…We have found that Salmeterol shows similar anti-inflammatory effects on PgLPS-stimulated macrophages [115]. Additionally, Feng et al have also shown neuroprotective effects of β-arrestin2 via endogenous opioid arrest in inflammatory microglial cells [116].…”

Effects of kappa opioid receptors on conditioned place aversion and social interaction in males and females

“…The p-p38 antibody we used has been used in immunoblot analyses in previous studies, and we confirmed its specificity in California mice. Kappa opioid receptor-microglia interactions can downregulate inflammatory signaling in the brain (Feng et al, 2013), but so far the behavioral implications of these interactions have received little attention.…”

Deficiency of β-Arrestin 2 in Dendritic Cells Contributes to Autoimmune Diseases

“…The increased number of double-positive cells in Arrb2 fl/fl Itgax-cre + mice suggested that the Ag-presenting and T cells priming these accumulating DCs contributed to the disease development. Discussion b-Arrestin 2 has been reported as a negative regulator of proinflammatory cytokine production, like IL-6 and TNF-a, by controlling NF-kB activation initiated by TLRs in many types of cells, such as chondrocytes, microglia, fibroblast-like synoviocytes, and splenocytes (44)(45)(46)(47). In RNA-seq, the upregulation of the genes related to positive regulation of IL-6 production and the TLR signaling pathway in Arrb2 2/2 DCs strongly supported the negative role of b-arrestin 2 in IL-6 production and also suggested that the regulation on NF-kB might be through the TLR signaling pathway.…”