Defining Dopamine‐Mediated Changes in NLRP1, NLRC5, NLRC4, and AIM2 Inflammasomes in Human Myeloid Cells

Abstract

Although the study of dopamine is most often associated with the regulation of reward and motor function, a growing body of research indicates that dopamine also acts as an immunomodulatory regulator. Our data show that dopamine can influence the secretion of inflammatory cytokines in myeloid cells such as macrophages and microglia. Specifically, we have shown that dopamine modulates inflammation in primary human monocyte‐derived macrophages (hMDM) through activation of the transcription factor NF‐κB and priming of the NLRP3 inflammasome, upregulating the expression of IL‐1 family cytokines (IL‐1β and IL‐18). However, the effect of dopamine on other proteins in the NLR family, including NLRP1, NLRC4, NLRC5, and AIM2, has not been defined. Each NLR protein is associated with a different inflammasome complex that has distinct activating stimuli, yet all inflammasomes mediate the secretion of IL‐1 family cytokines. We hypothesize that the effects of dopamine on different types of inflammasomes is distinct and may result in activation of discrete inflammatory pathways and/or differentially regulate cytokine secretion. To address this, we examined dopamine‐mediated changes in NLR proteins in both hMDM and a human microglial cell line (C20 cells). Our data indicate that in hMDM, dopamine upregulates expression of NLRC5, NLRC4, and AIM2 transcripts, while not changing NLRP1 mRNA expression. However, in microglia there was no expression of NLRC4 or AIM2, and dopamine downregulates NLRP1, while not changing NLRC5 mRNA expression. Ongoing work is using high‐content immunofluorescent imaging and Western blotting to analyze inflammasome protein expression in these myeloid cell models and determine how this correlates with NLR gene expression as well as dopamine receptor expression. Determining how dopamine affects NLR expression could improve our understanding of the role of dopamine and its receptors as drug targets in individuals with substance use disorders. Further, the activity of these inflammasomes is associated with a number of neuroimmunological diseases such as Parkinson’s, Alzheimer’s, multiple sclerosis and HIV that show disrupted dopamine signaling. Therefore, understanding the more specific immunologic actions of dopamine could initiate drug repurposing and the development of new therapeutic strategies based on manipulating dopamine’s effects on the immune system.