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Review
. 2021 Apr 9:12:663102.
doi: 10.3389/fimmu.2021.663102. eCollection 2021.

Immunomodulatory Effects of Dopamine in Inflammatory Diseases

Yifei Feng  1 , Yan Lu  1
Affiliations
Review

Immunomodulatory Effects of Dopamine in Inflammatory Diseases

Yifei Feng et al. Front Immunol. .

Abstract

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.

Keywords: Parkinson disease; dopamine; inflammation; inflammatory bowel disease; multiple sclerosis; rheumatoid arthritis; systemic lupus erythematosus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Roles that dopamine receptors play in regulating inflammasome formation as well as NF-κB pathway. (A) Elevated cAMP, induced by D1 like receptors, directly binds to NLRP3, triggering the ubiquitination of NLRP3 NACHT and LRR domains with K48 ubiquitin chains by MARCH7, targeting NLRP3 to autophagy-mediated degradation. (B) β-arrestin2 recruited by D2R binds to NLRP3 to repress its activation. (C) D5R directly recruits TRAF6, ARRB2, TAK1, IKKs, and PP2A to form a multiprotein complex, impairing TRAF6-mediated activation of NF-κB. (D) Activated cAMP/PKA/CREB signaling inhibits p65/RelA and p50 activation as well as their DNA binding by delaying IKB-α degradation and competing for the KIX binding site on CREB binding protein. (E) D2R signaling increases the level of CRYAB, which combines with NF-κB p65, thus negatively regulating the NF-κB signaling pathway. (F) D2R activation increases the expression of PPP2R2C, leading to PP2A and Akt dephosphorylation, and to the inhibition of the IKKα/IκBα/NF-κB signaling pathway.
Figure 2
Figure 2
Roles that dopamine receptors play in macrophages. (A)The activation of D2-like DRs can regulate the phagocytic activity of macrophages through β-arrestin2 pathway, and reduce the secretion of IL-2, IL-4, and IFN-γ. (B) LPS increases TNF - α production via TLRs and mediates activation of STAT3, which can be inhibited by D5R signaling. (C) Dopamine reduces the production of anti-inflammatory factor IL-10 through D5R. (D) D1R/cAMP/C/EBPϵ signaling increases IL-10 production, thus inhibiting LPS-mediated production of TNF-α.
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