S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

Abstract

Simple stress or necrotic cell death with subsequent release of damage-associated molecular patterns (DAMPs) is a characteristic feature of most advanced tumors. DAMPs within the tumor microenvironment stimulate tumor-associated cells, including dendritic cells and mesenchymal stromal cells (MSCs). The presence of tumor-infiltrating MSCs is associated with tumor progression and metastasis. Oxidized necrotic material loses its stimulatory capacity for MSCs. As a DAMP, S100A4 is sensitive to oxidation whereas uric acid (UA) acts primarily as an antioxidant. We tested these two biologic moieties separately and in combination for their activity on MSCs. Similar to necrotic tumor material, S100A4 and UA both dose-dependently induced chemotaxis of MSCs with synergistic effects when combined. Substituting for UA, alternative antioxidants (vitamin C, DTT, and N-acetylcysteine) also enhanced the chemotactic activity of S100A4 in a synergistic manner. This emphasizes the reducing potential of UA being, at least in part, responsible for the observed synergy. With regard to MSC proliferation, both S100A4 and UA inhibited MSCs without altering survival or inducing differentiation toward adipo-, osteo-, or chondrocytes. In the presence of S100A4 or UA, MSCs gained an immunosuppressive capability and stably induced IL-10– and IDO-expressing lymphocytes that maintained their phenotype following proliferation. We have thus demonstrated that both S100A4 and UA act as DAMPs and, as such, may play a critical role in promoting some aspects of MSC-associated immunoregulation. Our findings have implications for therapeutic approaches targeting the tumor microenvironment and addressing the immunosuppressive nature of unscheduled cell death within the tumor microenvironment.

Calcium-binding protein S100A4 confers mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis

“…Specifically, we found that IPF MPCs express higher levels of S100A4 compared with control MPCs (14). S100A4, a calcium binding protein, is upregulated in cancer stem cells, where it controls proliferation, differentiation, and metastasis (15)(16)(17)(18)(19)(20)(21)(22). S100A4 also amplifies TGF-β-induced fibroblast activation in the progressive fibrotic disorder systemic sclerosis (23).…”

“…While important, these studies are beyond the scope of the current body of work. S100A4 has also been termed metastasin because it regulates cancer cell metastasis (15)(16)(17)(18)(19)(20)(21)(22). While S100A4 levels are elevated in both cancer cells and IPF cells, IPF cells do not metastasize, suggesting that there are important differences between cancer and fibrosis in relation to S100A4 function.…”

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

“…It is constitutively present in all cells, but its levels increase following cell injury (63). It is the end product of purine nucleotide breakdown (64). Dying cells release uric acid extracellularly, which is then able to evoke immune responses such as the induction of dendritic cell maturation and increase in priming of CD8 T-cell responses to cross-presented antigens (65).…”

Uric acid priming in human monocytes is driven by the AKT–PRAS40 autophagy pathway

“…Nevertheless, an increasing body of evidence highlights the role of uric acid in diseases such as chronic kidney disease (11), fatty liver disease (12), cardiorenal syndrome and hypertension (13,14), coronary heart disease (15,16), type 2 diabetes (17), aging (18), and cancer (19), in addition to gout. The many associations of uric acid with common inflammatory diseases lead to a scenario of thrifty genes that currently predispose to fat storage disorders and systemic comorbidities (20).…”