Neuroinflammation and Parkinson’s disease 

　　Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by degeneration of dopaminergic neurons in the substantia nigra. Currently there is no effective treatment available that significantly delays the disease progression, due to our incomplete understanding of the mechanisms underlying neurodegeneration. It has been generally believed that PD results from the accumulation of mis-folded proteins in the substantia nigra. Although the pathogenesis of PD and other certain neurological diseases considered as “neuron-mediated” (Zhu, et al. PNAS, 2009; Yin, et al. J Neurosci, 2009; Zhu, et al. Nat Neurosci, 2015), emerging evidence has indicated that glial cells (astrocytes, microglia and NG2 glia) may play important roles in the onset and progression of PD. 

　　We found that in neurotoxin-induced animal models of PD, activation of astrocytic dopamine D2 receptor normally suppresses neuroinflammation in the striatum via an alphaB-crystallin-dependent manner. Thus, astrocytes likely play a previously unexpected but critical role in the modulation of neuroinflammation (Shao, et al. Nature, 2013). Consistent with this, astrocytic regulator of G protein signaling 5 (Rgs5) is recently shown to be a critical for astrocyte activation during neuroinflammation (Yin, et al. J Neuroinflamm, 2023). Moreover, NG2 glia, that are known as oligodendrocyte precursor cells, were identified as potent immunosuppressors of the brain innate immunity (Zhang, et al. BMC Med, 2009). We also showed the roles of distinct subpopulations of NG2+ microglia in microgliosis (Liu, et al. PNAS, 2023). We are currently investigating the roles of the gut-brain axis by using molecular and cellular biology approaches in combination with behavioral assays. These studies will help us to better understand the molecular and cellular basis of brain aging and neurodegenerative diseases, so that more effective therapeutic preventions and interventions will be established. 

　　Deregulation of CNS innate immunity and multiple sclerosis 

　　Autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD) are characterized by chronic and progressive neuroinflammation, demyelination and neurodegeneration. The mechanisms underlying the CNS immune response are not yet fully understood. Previously, we unraveled the role of activated astrocytes and its regulation in the pathogenesis of EAE, an animal model of MS. We showed the dopamine D2 receptor/6-pyruvoyl-tetrahydropterin synthase (PTS)–dependent mechanism for astrocyte driven CNS inflammation as a crucial signaling pathway in the regulation of pathogenesis of EAE, possibly also in MS (Lu, et al. J Exp Med, 2022). Recently, we demonstrated that dysregulated activities of the intestinal epithelium caused gut microbiota dysbiosis whereby influenced neuroinflammation and neurodegeneration in EAE via the gut-microbiota-brain axis in a female-biased manner (Peng et al. Immunity, 2023). We utilize a wide range of approaches in these projects including biochemistry, molecular and cellular biology techniques, integrated omic analysis, behavioral assays and mouse genetic models.