Purinergic Receptor P2Y12 Boosts Autoimmune Hepatitis Through Hexokinase 2-dependent Glycolysis in T Cells

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2023 Jul 27

PMID 37497007

Authors

Wei Zhuang

Xiucheng Liu

Guangyu Liu

Jie Lv

Hao Qin

Chun Wang

Ling Xie

Kaidireya Saimaier

Sanxing Han

Changjie Shi

Qiuhong Hua

Ru Zhang

Changsheng Du

Affiliations

Soon will be listed here.

Abstract

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.

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