Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease that causes mortality and morbidity worldwide. Recent studies suggest proinflammatory TH17 cells are key pathogenic factors that contribute to lupus nephritis. Our group previously demonstrate that microRNA-21 was highly upregulated in effector CD4+ T cells from both lupus patients and lupus-prone mice. However, the role of microRNA-21 in pathogenic TH17 cells and TH17 cell-mediated autoimmune diseases is still unclear. In this study, we systemically dissect the role of microRNA-21 in the differentiation and effector function of pathogenic TH17 cells and they-mediated autoimmune diseases.
MicroRNA-21 knockout and conditional knockout mice (CD11c-cre, Lyz2-cre, and CD4-cre) were generated for studying the role of microRNA-21 in the differentiation and effector function of TH17 cells. Experimental autoimmune encephalomyelitis (EAE) was induced to study the role of microRNA-21 in pathogenic TH17 cell-mediated autoimmune diseases. RNA-seq and DAVID bioinformatic analysis were conducted to find key microRNA-21 regulated pathway and molecular targets in pathogenic TH17 cells. Metabolomics study and metabolic assays were done to study the glycolytic activity of microRNA-21-deficent pathogenic TH17 cells.
In this study, we demonstrate that microRNA-21 induced by IL-6-STAT3 signaling targets the E3 ubiquitin ligase Peli1-c-Rel axis to promote effector and metabolic function of pathogenic TH17 cells. We demonstrate that microRNA-21 is not required for the development of intestinal homeostatic TH17 cells, but is essential for the maintenance of pathogenic TH17 cells in vivo. MicroRNA-21-deficient TH17 cells express less pathogenic TH17 signature genes and show less glycolytic activity. Many of the genes involved in glycolytic and related metabolic pathways are significantly downregulated in microRNA-21-deficient pathogenic TH17 cells, which include key transporters for glucose intake, Slc2a1/3 (Glut1/3), and rate-limiting enzymes, Hk1/2, Pfkl, Pgm2, Ldha and Pdk1. Interestingly, we find that non-pathogenic and pathogenic TH17 cells have greatly distinct metabolic states, with pathogenic TH17 cells highly glycolytic. We further show that conditional deletion of microRNA-21 in CD4+ T cells protects mice from EAE while loss of microRNA-21 expression by dendritic cells and myeloid cells do not.
To our knowledge, our study identifies the first evidence that by targeting the E3 ubiquitin ligase Peli1 microRNA-21 promotes the effector and metabolic function of pathogenic TH17 cells. Furthermore, the selective dependence of pathogenic TH17 cells on microRNA-21-mediated metabolic reprogramming has provided novel targets for therapeutic intervention of autoimmune and inflammatory diseases elicited by pathogenic TH17 cells.
To cite this abstract in AMA style:Yu X, Shen N. Microrna-21 Is a Critical Regulator of Autoimmunity through Promoting Effector and Metabolic Function of Pathogenic TH17 Cells [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/microrna-21-is-a-critical-regulator-of-autoimmunity-through-promoting-effector-and-metabolic-function-of-pathogenic-th17-cells/. Accessed September 24, 2021.
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