The receptor for advanced glycation endproducts (RAGE) modulates T cell signaling

Abstract

The receptor for advanced glycation endproducts (RAGE) is expressed in T cells after activation with antigen and is constitutively expressed in T cells from patients at-risk for and with type 1 diabetes mellitus (T1D). RAGE expression was associated with an activated T cell phenotype, leading us to examine whether RAGE is involved in T cell signaling. In primary CD4+ and CD8+ T cells from patients with T1D or healthy control subjects, RAGE-cells showed reduced phosphorylation of Erk. To study T cell receptor signaling in RAGE+ or-T cells, we compared signaling in RAGE+/+ Jurkat cells, Jurkat cells with RAGE eliminated by CRISPR/Cas9, or silenced with siRNA. In RAGE KO Jurkat cells, there was reduced phosphorylation of Zap70, Erk and MEK, but not Lck or CD3ξ. RAGE KO cells produced less IL-2 when activated with anti-CD3 +/-anti-CD28. Stimulation with PMA restored signaling and (with ionomycin) IL-2 production. Silencing RAGE with siRNA also decreased signaling. Our studies show that RAGE expression in human T cells is associated with an activated signaling cascade. These findings suggest a link between inflammatory products that are found in patients with diabetes, other autoimmune diseases, and inflammation that may enhance T cell reactivity.

Executable models of immune signaling pathways in HIV-associated atherosclerosis

“…However, to the best of our knowledge no study has attempted to holistically study the combined effects of variance in the numbers of specific immune cells and the cell-type specific signaling dysregulations (93). We found that in accordance with previous studies (19,(94)(95)(96)(97)(98)(99)(100), a population of CD8+ T cells was significantly increased in PBMCs from AS+ PLWH. However, contrary to our expectations (20,68,69,74,76,(101)(102)(103)(104), a population of monocytes was significantly decreased in PBMCs from AS+ PLWH.…”

Receptor Mediated Effects of Advanced Glycation End Products (AGEs) on Innate and Adaptative Immunity: Relevance for Food Allergy

“…Food proteins through interaction with pathogen recognition receptors (PRR), which includes macrophage scavenger receptors and RAGE, may modulate additional downstream immunological effects promoting T cell activation and differentiation, leading to Th2 responses in food allergies [45,83]. Further potential immunological modulatory effects of AGEs include the ability to create novel epitopes that are recognized by IgE, the capacity to enhance inflammatory conditions as well as oxidative stress, and causing a reduction in the diversity of the intestinal flora which is associated with an enhanced susceptibility to allergies [17,46,53,64,66,72,[81][82][83][84][85].…”

“…This not only has the capacity for contributing to low-grade inflammation and local inflammation in tissues expressing RAGE but also to food allergies, since the induction of oxidative stress and enhanced cytokine expression are consequences of this binding (as shown in Figure 4) [82]. Food proteins through interaction with pathogen recognition receptors (PRR), which includes macrophage scavenger receptors and RAGE, may modulate additional downstream immunological effects promoting T cell activation and differentiation, leading to Regarding the immunogenicity of AGEs through receptor recognition, it is crucial to note that some receptors, such as RAGE, only bind the AGEs and produce cytokine as a result, but other receptors, such as galectin-3, also internalize the proteins, leading to enhanced antigen presentation of the protein to which the AGEs are bound, which may lead to the activation of food protein-specific T cells [72,83,86,87]. Therefore, the initiation of adaptative immunity by AGEs will occur indirectly via antigen presentation, ultimately leading to T-cell activation.…”

“…Recently, it has been shown that the RAGE expressed on T cells is involved in the activation of the T-cell signaling cascade and may be an important mechanism in the response of T cells to inflammatory mediators. This suggests that RAGE may also play a role in the direct activation of T cells via AGEs present in the circulation, contributing to inflammation and enhanced T-cell reactivity [83].…”

RAGE pathway activation and function in chronic kidney disease and COVID-19

“…AGE-exposed human podocytes in vitro induce NOTCH1 cleavage and formation of NICD1 through the production of γ-secretase ( 35 ). RAGE activation also promotes Th1 immunity ( 90 ). In a preprint involving children with SARS-CoV-2-associated multisystem inflammatory syndrome, T-regulatory cells express increased cell surface NOTCH1, which reduces their suppressive functions ( 91 ).…”