CD8+ T Cells Involved in Metabolic Inflammation in Visceral Adipose Tissue and Liver of Transgenic Pigs.

Abstract

Anti-inflammatory therapies have the potential to become an effective treatment for obesity-related diseases. However, the huge gap of immune system between human and rodent leads to limitations of drug discovery. This work aims at constructing a transgenic pig model with higher risk of metabolic diseases and outlining the immune responses at the early stage of metaflammation by transcriptomic strategy. We used CRISPR/Cas9 techniques to targeted knock-in three humanized disease risk genes, GIPRdn , hIAPP and PNPLA3I148M . Transgenic effect increased the risk of metabolic disorders. Triple-transgenic pigs with short-term diet intervention showed early symptoms of type 2 diabetes, including glucose intolerance, pancreatic lipid infiltration, islet hypertrophy, hepatic lobular inflammation and adipose tissue inflammation. Molecular pathways related to CD8+ T cell function were significantly activated in the liver and visceral adipose samples from triple-transgenic pigs, including antigen processing and presentation, T-cell receptor signaling, co-stimulation, cytotoxicity, and cytokine and chemokine secretion. The similar pro-inflammatory signaling in liver and visceral adipose tissue indicated that there might be a potential immune crosstalk between the two tissues. Moreover, genes that functionally related to liver antioxidant activity, mitochondrial function and extracellular matrix showed distinct expression between the two groups, indicating metabolic stress in transgenic pigs' liver samples. We confirmed that triple-transgenic pigs had high coincidence with human metabolic diseases, especially in the scope of inflammatory signaling at early stage metaflammation. Taken together, this study provides a valuable large animal model for the clinical study of metaflammation and metabolic diseases.

• Authors: Kaiyi Zhang, Cong Tao, Jianping Xu, Jinxue Ruan, Jihan Xia, Wenjuan Zhu, Leilei Xin, Huaqiong Ye, Ning Xie, Boce Xia, Chenxiao Li, Tianwen Wu, Yanfang Wang, Martine Schroyen, Xinhua Xiao, Jiangao Fan, Shulin Yang
• Journal: Frontiers in immunology (Front Immunol) Vol. 12 Pg. 690069 ( 2021) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 34322121 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Zhang, Tao, Xu, Ruan, Xia, Zhu, Xin, Ye, Xie, Xia, Li, Wu, Wang, Schroyen, Xiao, Fan and Yang.

Chemical References

• APP protein, human
• Amyloid beta-Protein Precursor
• Blood Glucose
• Cytokines
• Inflammation Mediators
• Lipids
• Membrane Proteins
• Receptors, Gastrointestinal Hormone
• gastric inhibitory polypeptide receptor
• Lipase
• adiponutrin, human

Topics

• Amyloid beta-Protein Precursor (genetics)
• Animals
• Animals, Genetically Modified
• Blood Glucose (metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cytokines (genetics, metabolism)
• Diabetes Mellitus, Type 2 (genetics, immunology, metabolism, pathology)
• Disease Models, Animal
• Inflammation Mediators (metabolism)
• Intra-Abdominal Fat (immunology, metabolism, pathology)
• Islets of Langerhans (immunology, metabolism, pathology)
• Lipase (genetics)
• Lipids (blood)
• Liver (immunology, metabolism, pathology)
• Lymphocyte Activation
• Male
• Membrane Proteins (genetics)
• Non-alcoholic Fatty Liver Disease (genetics, immunology, metabolism, pathology)
• Receptors, Gastrointestinal Hormone (genetics)
• Swine (genetics)
• Transcriptome