2. Academic Validation
  3. Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications

Regulation of autoimmune disease progression by Pik3ip1 through metabolic reprogramming in T cells and therapeutic implications

  • Sci Adv. 2022 Sep 30;8(39):eabo4250. doi: 10.1126/sciadv.abo4250.
Wenqiang Xie 1,  Juan Fang 1,  Zhongyan Shan 1,  Junyi Guo 1,  Yuan Liao 2,  Zhaolei Zou 1,  Jun Wang 3,  Shuqiong Wen 1,  Lisa Yang 1,  Yanshu Zhang 1,  Huanzi Lu 1,  Hang Zhao 4,  Dong-Ming Kuang 5,  Peng Huang 6,  Qianming Chen 7,  Zhi Wang 1
Affiliations

Affiliations

  • 1 Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guangzhou 510055, China.
  • 2 Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.
  • 4 State Key Laboratory of Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
  • 5 Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 6 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
  • 7 School of Stomatology, Zhejiang University School of Medicine, Hangzhou, China.
PMID: 36179018 DOI: 10.1126/sciadv.abo4250
Abstract

Metabolic alterations could profoundly affect immune functions and influence the progression and outcome of autoimmune diseases. However, the detailed mechanisms and their therapeutic potential remain to be defined. Here, we show that phosphatidylinositide 3-kinase interacting protein 1 (Pik3ip1), a newly identified negative immune regulator, is notably down-regulated in several major autoimmune diseases through a previously unidentified mechanism mediated by interleukin-21/p38 mitogen-activated protein kinase/a disintegrin and metalloprotease-17 (ADAM17) pathway. Down-regulation of Pik3ip1 in T cells causes a major metabolic shift from Oxidative Phosphorylation toward aerobic glycolysis, leading to their overactivation and aggressive disease progression in experimental autoimmune encephalomyelitis (EAE) mouse model. Suppression of hypoxia-inducible factor 1α (Hif1α) or pharmacologic inhibition of glycolysis could reverse these phenotypes and largely mitigate EAE severity. Our study reveals a previously unrecognized role of Pik3ip1 in metabolic regulation that substantially affects the inflammatory loop in the autoimmune setting and identifies the Pik3ip1/Hif1α/glycolysis axis as a potential therapeutic target for treatment of autoimmune diseases.

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