IADR Abstract Archives
Regulation of Autoimmune Disease Progression by Pik3ip1 Through Metabolic Reprogramming
Objectives: Compelling evidence suggests that metabolic alterations could profoundly affect immune functions and influence the progression and outcome of autoimmune diseases. However, the detail mechanisms by which metabolic regulation impact autoimmune diseases and its therapeutic potential remain to be defined. We investigated whether Pik3ip1, a novel negative immune regulator, was involved in T-cell metabolic regulation and its role in the polarization of pro-inflammatory T cells during autoimmunity.
Methods: To assess the role of Pik3ip1 in the context of autoimmunity, we compared the expression of Pik3ip1 on PBMCs from patients with multiple autoimmune disorders with that on PBMCs from healthy donors and examined the correlation between Pik3ip1 expression and disease severity and treatment response. Furthermore, we used the experimental autoimmune encephalomyelitis (EAE) model to test the effect of genetic Pik3ip1 disruption on T cells in this setting. In addition, by performing RNA sequencing and seahorse mitochondrial stress test, we explored the mechanisms of Pik3ip1 deficiency on autoimmune disease progression, which was further validated by fluorescence microscopy and flow cytometry.
Results: The expression of Pik3ip1 was significantly down-regulated in several major autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis through a novel mechanism mediated by IL-21/p38/ADAM17 pathway. The down-regulation of Pik3ip1 were highly correlated with more severe clinical disease and poor treatment response. Mechanistically, the downregulation of Pik3ip1 in T cells caused a significant upregulation of hypoxia inducible factor 1α (Hif1α), leading to major metabolic shift in favor of aerobic glycolysis and T-cell over activation, which significantly exacerbated disease progression in EAE model. In contrast, suppression of Hif1α or pharmacologic inhibition of glycolysis could reverse the metabolic abnormality due to Pik3ip1 loss, and largely mitigate EAE severity.
Conclusions: These findings establish Pik3ip1 as a key regulator of T-cell metabolic homeostasis and highlight the importance of Pik3ip1/Hif1α/glycolysis axis in autoimmune diseases.
Methods: To assess the role of Pik3ip1 in the context of autoimmunity, we compared the expression of Pik3ip1 on PBMCs from patients with multiple autoimmune disorders with that on PBMCs from healthy donors and examined the correlation between Pik3ip1 expression and disease severity and treatment response. Furthermore, we used the experimental autoimmune encephalomyelitis (EAE) model to test the effect of genetic Pik3ip1 disruption on T cells in this setting. In addition, by performing RNA sequencing and seahorse mitochondrial stress test, we explored the mechanisms of Pik3ip1 deficiency on autoimmune disease progression, which was further validated by fluorescence microscopy and flow cytometry.
Results: The expression of Pik3ip1 was significantly down-regulated in several major autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis through a novel mechanism mediated by IL-21/p38/ADAM17 pathway. The down-regulation of Pik3ip1 were highly correlated with more severe clinical disease and poor treatment response. Mechanistically, the downregulation of Pik3ip1 in T cells caused a significant upregulation of hypoxia inducible factor 1α (Hif1α), leading to major metabolic shift in favor of aerobic glycolysis and T-cell over activation, which significantly exacerbated disease progression in EAE model. In contrast, suppression of Hif1α or pharmacologic inhibition of glycolysis could reverse the metabolic abnormality due to Pik3ip1 loss, and largely mitigate EAE severity.
Conclusions: These findings establish Pik3ip1 as a key regulator of T-cell metabolic homeostasis and highlight the importance of Pik3ip1/Hif1α/glycolysis axis in autoimmune diseases.