Editors' ChoiceInflammation

Turning down inflammation with dopamine

Sci. Signal.  03 Feb 2015:
Vol. 8, Issue 362, pp. ec25
DOI: 10.1126/scisignal.aaa8155

Inflammasomes are intracellular protein complexes that activate immune responses in response to infection or detection of endogenous “danger” signals. Formation of the NLRP3 inflammasome activates caspase-1, enabling the production of mature cytokines such as interleukin-1β (IL-1β), and is implicated in pathological inflammatory responses in the periphery and the brain. Dopamine is both a neurotransmitter and a peripheral chemical mediator, and dopamine receptors are present on most types of immune cells. Yan et al. found that dopamine or a dopamine receptor 1 (DRD1) agonist inhibited NLRP3-mediated activation of caspase1 and release of IL-1β from primed bone marrow–derived macrophages (BMDMs). Dopamine was ineffective in BMDMs from Drd1-/- mice or if DRD1 was knocked down. Dopamine or the DRD1 agonist stimulated the ubiquitylation and autophagosomal degradation of NLRP3, responses that required DRD1-mediated stimulation of adenylate cyclase and adenosine 3′,5′-monophosphate (cAMP). Unexpectedly, pharmacological analysis suggested that neither protein kinase A nor the cAMP-regulated guanine nucleotide exchange factor EPAC were involved. Immunoprecipitation analysis suggested that cAMP may bind directly to NLRP3. Mass spectrometry analysis identified 3 candidate E3 ubiquitin ligases, and knockdown experiments indicated that one of these, MARCH7, was required for the dopamine-induced ubiquitylation and degradation of NLRP3. Nlrp3-/- mice were protected from MPTP-induced loss of nigral dopaminergic neurons (a model of Parkinson’s disease), whereas Drd1-/- mice exhibited more severe loss. Caspase1 activation and IL-1β abundance in the brains of the MPTP-treated Drd1-/- mice were also increased, consistent with an anti-inflammatory effect of dopamine in the brain through the suppression of NLRP3 activation. Administration of a DRD1 agonist prior to MPTP reduced loss of dopaminergic neurons, IL-1β abundance, and caspase1 activation. Induction of inflammatory responses in the periphery were also blunted by dopamine in response to lipopolysaccharide or peritoneal injection of monosodium urate, and this anti-inflammatory effect required DRD1 and was associated with reduced IL-1β and induction of NLRP3 ubiquitylation and degradation. Thus, agonists of DRD1 may be an effective strategy for limiting pathological inflammation.

Y. Yan, W. Jiang, L. Liu, X. Wang, C. Ding, Z. Tian, R. Zhou, Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 62–73 (2015). [PubMed]

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