1. Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
2. Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
3. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
4. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China.
5. Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Shanghai, 200040, China.
*These authors contributed equally to this work.
Increasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4+ and CD8+ effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.
Keywords: P2RY12, autoimmune hepatitis, T cell metabolism, glycolysis, HK2