Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome

Inflammasomes are involved in diverse inflammatory diseases, so the activation of inflammasomes needs to be tightly controlled to prevent excessive inflammation. However, the endogenous regulatory mechanisms of inflammasome activation are still unclear. Here, we report that the neurotransmitter dopamine (DA) inhibits NLRP3 inflammasome activation via dopamine D1 receptor (DRD1). DRD1 signaling negatively regulates NLRP3 inflammasome via a second messenger cyclic adenosine monophosphate (cAMP), which binds to NLRP3 and promotes its ubiquitination and degradation via the E3 ubiquitin ligase MARCH7. Importantly, in vivo data show that DA and DRD1 signaling prevent NLRP3 inflammasome-dependent inflammation, including neurotoxin-induced neuroinflammation, LPS-induced systemic inflammation, and monosodium urate crystal (MSU)-induced peritoneal inflammation. Taken together, our results reveal an endogenous mechanism of inflammasome regulation and suggest DRD1 as a potential target for the treatment of NLRP3 inflammasome-driven diseases.