Changpu Yujin Decoction Alleviates Tourette Syndrome by Modulating Lipid Metabolism and Microglial Polarization: Involvement of the TREM2/NF-κB Signaling Axis

Background: Changpu Yujin Decoction (CPYJD) has been clinically utilized for more than ten years as an effective herbal formula for Tourette syndrome (TS). However, the exact mechanism by which CPYJD treats TS via modulating lipid metabolism and microglia (MG) polarization remains unclear. Methods: A combination of in vivo and in vitro experiments was employed. A total of 72 three-week-old Sprague–Dawley (SD) rats were divided into a control group (n = 12) and a modeling group (n = 60). After successful model establishment, the modeled rats were randomly divided into five groups (n = 12 per group): the model group, the tiapride group, and the low-dose, medium-dose, and high-dose Changpu Yujin Decoction (CPYJD-L, CPYJD-M, and CPYJD-H, respectively) groups. All groups were administered the corresponding treatments for 28 consecutive days, and therapeutic efficacy was evaluated by behavioral scoring after the intervention. Neuronal morphology and myelin structure were observed by hematoxylin–eosin (HE) staining, Nissl staining, and transmission electron microscopy (TEM). The expression of lipid metabolism- and microglial phenotype-related indicators in each group was detected by immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), biochemical assays, reverse transcription quantitative PCR (RT-qPCR), and Western blotting (WB). In addition, lipidomics analysis was performed to identify differential lipid metabolites. For the in vitro experiments, triggering receptor expressed on myeloid cells 2 (TREM2) was knocked down in BV2 cells using small interfering RNA (siRNA), and inflammation was induced by lipopolysaccharide (LPS). The cells were divided into a control group, an LPS group, a CPYJD-medicated serum group, a TREM2 knockdown group, and a TREM2 knockdown plus CPYJD-medicated serum group. Cell morphology was observed under a microscope, and lipid metabolism- and microglial phenotype-related indicators in each group were detected by immunofluorescence, biochemical assays, RT-qPCR, and WB. Results: Compared with the control group, rats in the model group exhibited significantly increased locomotor activity and stereotyped behaviors, injured striatal neurons with myelin damage, abnormal lipid metabolism and lipid accumulation, an enhanced M1-like pro-inflammatory phenotype with elevated inflammatory cytokine levels, downregulated TREM2 expression, and activation of the nuclear factor kappa-B (NF-κB) signaling pathway. CPYJD reduced stereotyped behaviors and locomotor activity in TS model rats, alleviated neuronal and myelin injury, improved lipid metabolic abnormalities and lipid accumulation, enhanced the M2-like anti-inflammatory phenotype, reduced inflammatory cytokine levels, and upregulated TREM2 expression while inhibiting the activation of the NF-κB signaling pathway. TREM2 knockdown aggravated lipid metabolic abnormalities, lipid accumulation, and the expression of M1-like pro-inflammatory phenotype-related factors in BV2 cells, whereas CPYJD-medicated serum reversed these changes. Conclusions: CPYJD ameliorated pathological injury of striatal neurons, improved lipid metabolic abnormalities and lipid accumulation in MG, promoted a shift in MG from the M1-like pro-inflammatory phenotype toward the M2-like anti-inflammatory phenotype, and reduced inflammatory cytokine levels, thereby alleviating tic symptoms in TS model rats. These effects may be associated with the involvement of the TREM2/NF-κB signaling axis.