Urate crystals directly activate the T-cell receptor complex and induce T-cell proliferation

Abstract

Abstract. Uric acid is a known danger associated molecular pattern molecule able to induce inflammation following internalization of its crystals by cells of the innate immune system. By activating antigen-presenting cells, urate boosts adaptive immunity as well. Furthermore, urate crystals can induce proliferation of isolated T-cells, which are unable to phagocytose crystal particles. In light of the evidence that urate crystals can also activate dendritic cells and macrophages without prior internalization but through sequestration of lipid rafts (and consequently receptors clustering in a non specific manner), the authors evaluated whether such a mechanism is involved in the direct activation of T-cells by urate crystals. In the present study, isolated human T-cells were cultured with or without urate at a concentration above its crystallization level. The expression and phosphorylation state of the T-cell receptor (TCR) complex zeta chain and the expression of the master regulator of cell proliferation c-Myc were assessed by western blotting. T-cell proliferation was measured by bromodeoxyuridine assay. Collectively, the results indicated that urate increased zeta chain phosphorylation indicating that it induces activation of TCR complex directly, since zeta chain phosphorylation takes place at the cell membrane and is a very proximal event in TCR complex-mediated signal transduction. In parallel, urate increased the expression of the transcription factor c-Myc and induced T-cell proliferation. In conclusion, urate crystals directly activate the TCR complex and induce T-cell proliferation.

Changes in aging-induced kidney dysfunction in mice based on a metabolomics analysis

“…Our study demonstrated that purine metabolism was disrupted in the metabolic pathway of aging-induced kidney dysfunction in which the xanthine content was elevated in aging mice. Studies have found that the mechanisms of kidney injury caused by abnormal uric acid increase primarily include oxidative stress, endothelial dysfunction, kidney fibrosis, and inflammation ( 37 – 40 ). Uric acid is not only a marker of kidney disease but also a potential therapeutic target.…”

Sideroxylin (Callistemon lanceolatus) suppressed cell proliferation and increased apoptosis in ovarian cancer cells accompanied by mitochondrial dysfunction, the generation of reactive oxygen species, and an increase of lipid peroxidation

“…In the apoptotic events that mitigate cancer progression, the changes in mitochondrial function influence cell viability, metabolism, gene expression, mitochondrial membrane permeability, and redox processes (Boland, Chourasia, & Macleod, 2013). The mitochondrial transmembrane potential (MMP, Δψ) was affected by the extrinsic and intrinsic stress stimuli of chemotherapy, which led to cell death, and the formation of the mitochondria permeability transition pore complex, which led to loss of MMP; these changes induce cytochrome c-dependent caspase activation and pro-apoptotic proteins in cancer cells (Eleftheriadis, Pissas, Liakopoulos, & Stefanidis, 2016). In accordance with previous studies, sideroxylin induced the loss of MMP during the cell death process in both cell types in the present study.…”

Uric acid and inflammation in kidney disease

“…In addition, some studies have shown that uric acid directly activates T cells in an antigen-independent manner. An experiment using human T cells isolated from healthy human blood samples revealed that uric acid not only increased CD25 expression and NRLP3 inflammasome-dependent IL-1␤ secretion but also induced T cell proliferation (27)(28)(29)151). When these observations are taken together, it becomes evident that uric acid alarms the immune system by stimulating dendritic cells, macrophages, and T cells (Fig.…”