EXPLORE THE ROLE OF INFLAMMATORY PATHWAY OF TNFR1 IN ALCOHOL DEPENDENCE AND THE POTENTIAL TO DIFFERENTIATE DELIRIUM TREMENS

Abstract Background Inflammatory factor TNF-alpha has been implicated in the pathophysiology of alcohol withdrawal syndrome (AWS) and craving phenomenon in relation to alcohol dependence (AD) [1]. Its binding to TNF receptor 1 (TNFR1) has also been reported to be involved in the apoptosis pathway [2] and to lead to neuronal cell death. Delirium tremens (DT) is a serious subtype of AWS and associated with high mortality if inadequately treated. Little is known about the role of the soluble form TNFR1 (sTNFR1) in patients with AD and its relationship with DT. Aims & Objectives This study aimed to compare sTNFR1 levels in patients with AD who experience DT during withdrawal to those without DT, in comparison to healthy controls. Method A total of 224 patients with AD who were admitted for alcohol detoxification treatment and 117 non- AD controls were recruited. Blood levels of sTNFR1, and the inflammatory C-C motif chemokine ligand 11 (CCL11) were evaluated using enzyme-linked immunosorbent assay (ELISA). In patients with AD, we assessed various alcohol-related variables, including, Obsessive Compulsive Drinking Scale (OCDS) scores, Penn Alcohol Craving Score (PACS), Clinical Institute Withdrawal Assessment for Alcohol Scale, revised (CIWA-Ar) scores, and Alcohol Craving Questionnaire-Short Form-Revised total score (ACQ-SF-R). Results The AD group exhibited lower body mass index (BMI) and fewer years of education, but had higher rates of cigarette smoking, as well as elevated plasma CCL11 [3] and sTNFR1 levels compared to age and sex- matched controls (Mann-Whitney U test, P<0.0001). Within the AD group, 11.2% (n = 25) experienced DT during their admission, referred to as the DT group. The DT group exhibited significantly higher levels of sTNFR1 (P<0.0001) compared to the non-DT group. In addition, the DT group was characterized by older age (P≦0.023), elevated plasma CCL11 levels (P=0.049), and more severe withdrawal symptoms, as indicated by CIWA-Ar scores (P≦0.0002). They also displayed greater craving, as reflected in OCDS total scores (P≦0.009), as well as PACS (P≦0.01) and ACQ-SF-R (P≦0.011) scores. Multiple linear regression analysis showed that sTNFR1 was significantly correlated with the occurrence of DT (partial r2=0.039, P=0.003), as well as OCDS total (partial r2=0.091, P≦0.0003) and plasma CCL11 levels (partial r2 =0.028, P≦0.008). Furthermore, the receiver operating characteristic (ROC) curve demonstrated that an sTNFR1 level of 1,050 pg/mL could effectively differentiate the DT group from the non-DT group (area under the ROC curve: 0.79; sensitivity: 96.0%, specificity: 56.3%, p <0.001). Discussion & Conclusion These results indicate that AD patients with DT exhibited higher levels of inflammation, as evidenced by increased plasma levels of sTNFR1 and CCL-11. Furthermore, sTNFR1 may have the potential to discriminate those with development of DT. In conclusion, these findings suggest that sTNFR1 plays a role in the neurobiological mechanisms underlying AD and modifying the phenotype of DT. References 1.Alvarez Cooper, I., et al., Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder. Brain Plast, 2020. 6(1): p. 47-66. 2.Micheau, O. and J. Tschopp, Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell, 2003. 114(2): p. 181-90. 3.Huang, M.C., et al., Increase in plasma CCL11 (Eotaxin-1) in patients with alcohol dependence and changes during detoxification. Brain Behav Immun, 2022. 99: p. 83-90.