Dopamine transporter activity regulates neuroimmune communication

Abstract

ID 52323Poster Board 370 Dopamine transporter (DAT) is a master regulator of dopamine transmission in the brain. Mutation in DAT structure is implicated in familial Parkinson's disease. In addition, DAT is one of the main targets of psychostimulants, therefore, DAT is conventionally studied in central nervous system (CNS) and in the context of neurological and neuropsychiatric diseases. But, in addition to the brain, DAT is also expressed at the plasma membrane of myeloid and lymphoid cells in the periphery. We found DAT activity reduces macrophage responses to immune stimulation through autocrine/paracrine signaling. In human monocyte-derived macrophages, we identified an immunosuppressive role for DAT, where inhibition of DAT activity exaggerated macrophages' phagocytic response and enhanced production of inflammatory mediators such as IL-6, CCL2, and TNFa. Consistent with our ex-vivo studies, our in vivo data in a mouse model with genetic deletion of DAT (DAT KO) also showed an immunosuppressive role for DAT. Unlike WT littermates, LPS-induced immune stimulation in DAT KO mice resulted in elevated baseline inflammation, exaggerated phagocytosis, increased B-cell and T-cell responses. In addition, our studies in 96 PD patients and mouse models of PD revealed the disease relevance of increased DAT activity as measured by increased number of DAT expressing monocytic suppressor cells. These data collectively point to the importance of DAT activity in peripheral immune responses. Our current and ongoing studies seek to determine the impact of DAT deletion and its restoration on the CNS immune landscape and the ensuing changes in peripheral immunity. We will first determine whether DAT deletion and/or LPS-mediated immune stimulation alters microglial number, morphology, and their contact with dopaminergic nuclei in DAT-expressing brain regions such as midbrain, striatum, median forebrain bundle and hypothalamus. To determine which dopaminergic nuclei is critical for top-down (CNSperiphery) regulation of peripheral immunity, we will virally restore DAT in each brain region and monitor peripheral immunity, as described above. The completion of this study will reveal the contribution of DAT activity in the regulation of CNS-to-periphery neuroimmune interactions, providing a key opening into a new field for dopamine transporter biology.