Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation

Wu, Yuqing; Hu, Yunzhang; Wang, Bingwei; Li, Sheng; Ma, Chunmei; Li, Xue; Moynagh, Paul N.; Zhou, Jiawei; Yang, Shuo

doi:10.1016/j.molcel.2020.01.022

Cited by 67 publications

(62 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the role of dopamine in systemic inflammation is widely recognized, only recently it was shown that dopamine inhibits TRAF6-mediated NF-κB activation and inflammation via the D5 dopamine receptor in macrophages [ 185 ]. Through this mechanism, dopamine protected mice against S. aureus -induced sepsis and meningitis.…”

Section: The Immunomodulatory Role Of Dopaminementioning

confidence: 99%

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Pajares

Rojo

Manda

et al. 2020

Cells

484

296

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a common neurodegenerative disorder primarily characterized by the death of dopaminergic neurons that project from the substantia nigra pars compacta. Although the molecular bases for PD development are still little defined, extensive evidence from human samples and animal models support the involvement of inflammation in onset or progression. However, the exact trigger for this response remains unclear. Here, we provide a systematic review of the cellular mediators, i.e., microglia, astroglia and endothelial cells. We also discuss the genetic and transcriptional control of inflammation in PD and the immunomodulatory role of dopamine and reactive oxygen species. Finally, we summarize the preclinical and clinical approaches targeting neuroinflammation in PD.

show abstract

Section: The Immunomodulatory Role Of Dopaminementioning

confidence: 99%

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Pajares

Rojo

Manda

et al. 2020

Cells

484

296

View full text Add to dashboard Cite

show abstract

“…D5R inhibits NF-kB signaling by mediating the negative regulation of ARRB2/PP2A on TRAF6-dependent signaling. A study found that D5R, via the EFD and IYX(X)I/L motifs in its CT and IC3 loop, respectively, can directly recruit TRAF6 and its negative regulator ARRB2, as well as downstream signaling proteins, such as TAK1, IKKs, and PP2A, to form a multiprotein complex, which impairs TRAF6-mediated activation of NF-kB (91).…”

Section: Nf-kb Signalingmentioning

confidence: 99%

Immunomodulatory Effects of Dopamine in Inflammatory Diseases

Feng

Lü

2021

Front. Immunol.

View full text Add to dashboard Cite

Dopamine (DA) receptor, a significant G protein-coupled receptor, is classified into two families: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor families, with further formation of homodimers, heteromers, and receptor mosaic. Increasing evidence suggests that the immune system can be affected by the nervous system and neurotransmitters, such as dopamine. Recently, the role of the DA receptor in inflammation has been widely studied, mainly focusing on NLRP3 inflammasome, NF-κB pathway, and immune cells. This article provides a brief review of the structures, functions, and signaling pathways of DA receptors and their relationships with inflammation. With detailed descriptions of their roles in Parkinson disease, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, this article provides a theoretical basis for drug development targeting DA receptors in inflammatory diseases.

show abstract

“…Dopamine receptors are important players in the regulation of inflammation in the brain levels [39]. Recently, DRD5 has been shown to inhibit NF-kB activation and modulate levels of inflammation [40]. The increased DRD5 expression induced by ONC201 might reflect the contribution of this receptor signaling in returning macrophages to homeostasis after ONC201 treatment.…”

Section: Discussionmentioning

confidence: 99%

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

et al. 2021

View full text Add to dashboard Cite

Tumor-associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro-inflammatory switch in primary human monocyte-derived macrophages that reactivates their antitumor activities, thus enhancing the onco-toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages responded to ONC201 with a severe loss of mitochondria integrity, a switch to glycolytic ATP production, alterations in glutamate transport, and a shift towards a pro-inflammatory profile. Treatment of macrophages-glioblastoma cells co-cultures with ONC201 induced similar alterations in glutamatergic and inflammatory gene expression profiles of macrophages. It induced as well metabolic changes and a proinflammatory switch of the co-culture milieu. However, these changes did not translate into increased onco-toxicity. This study provides the first evidence that ONC201 affects macrophage immunometabolism and leads to a pro-inflammatory tumor environment. This speaks in favor of implementing ONC201 in combinatorial therapies and warrants further investigation of the mechanisms of action of ONC201 in macrophages and other immune cells.

show abstract

Dopamine Uses the DRD5-ARRB2-PP2A Signaling Axis to Block the TRAF6-Mediated NF-κB Pathway and Suppress Systemic Inflammation

Cited by 67 publications

References 41 publications

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications

Immunomodulatory Effects of Dopamine in Inflammatory Diseases

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

Contact Info

Product

Resources

About