Diabetes and other autoimmune endocrine diseases
The receptor for advanced glycation endproducts (RAGE) may be found in adaptive immune cells but its role is not understood. Patients with type 1 diabetes (T1D) express increased levels of intracellular RAGE in T cells, compared to healthy controls, as do euglycemic at-risk relatives who progress to disease. We studied gene expression by nanostring in T cells from type 1 diabetics and found differences in pathways utilized by RAGE+ versus RAGE- T cells including those affecting apoptosis and survival via TNFs/NF-κB/Bcl-2 proteins, IL-12-induced IFN-γ production, and PDGF signaling through STATs and NF-κB proteins.
We studied RAGE signaling in Jurkat cells. We silenced intracellular RAGE with pooled siRNAs causing a 75% reduction in RAGE by flow cytometry FITC mean fluorescence index. Using knockdowns, we found T cell receptor (TCR) signaling interference. Western blots of RAGE siRNA transfected Jurkats showed decreased baseline levels of Zap70. There was decreased signal amplitude of phosphorylated Erk 1/2 with RAGE siRNA. The addition of high mobility group box 1 protein (HMGB1), a known RAGE ligand, increased the amplitude of phosphorylated Erk 1/2 signal in submaximally stimulated Jurkats transfected with negative control siRNA but not with RAGE silencing. RAGE siRNA did not affect CD3 surface expression.
RAGE stimulation may enhance TCR signal in T cells. Through the release of multiple ligands during inflammation this mechanisms may facilitate survival and activation of T cells.
Howard Hughes Medical Institute, Yale School of Medicine
Professor of Immunology
Department of Immunobiology and Internal Medicine, Yale University