D-mannose induces regulatory T cells and suppresses immunopathology

Abstract

D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3 regulatory T cells (T cells) in mice. In vitro, D-mannose stimulated T cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αβ and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

“…Recently, D-mannose treatment increased ROS production in T cells compared with TCR stimulation alone. 52 In line with our results, blockade of ROS activity by NAC significantly reduced numbers of Dmannose-induced Treg cells. 52 Although ROS have been considered toxic products of cellular metabolism, increasing evidence supports the idea that low amounts of ROS are positive contributors to normal signalling pathways.…”

Mannose Alters Gut Microbiome, Prevents Diet-Induced Obesity, and Improves Host Metabolism

“…Mannose can be taken up by all host cells (Sharma and Freeze, 2011) but may have a cell-type-specific effect that influences fat absorption and/or metabolism either directly or indirectly. A recent study has shown mannose supplementation of non-obese diabetic mice prevents onset of diabetes by increasing the number of T reg cells (Zhang et al, 2017). …”

Immune cell metabolism in autoimmunity

“…Elevated levels of adipocyte-fatty acid binding protein (FABP), which is responsible for facilitating the transport of fatty acids to specific organelles for oxidation, correlate with disease activity in patients with multiple sclerosis (MS) and clinical isolated syndrome [81]. Finally, D-mannose was found to induce T reg differentiation and decrease the production of inflammatory cytokines, indicating that D-mannose has the potential to improve autoimmune pathology [83]. Finally, D-mannose was found to induce T reg differentiation and decrease the production of inflammatory cytokines, indicating that D-mannose has the potential to improve autoimmune pathology [83].…”

“…Inhibition of FABP prevented EAE in mice [82], providing a possible treatment option to correct this specific metabolic defect that is contributing to immune cell dysfunction in MS-related diseases. Mechanistically, D-mannose promotes transforming growth factor (TGF)-β production, which is mediated at least in part through ROS produced by increased FAO, an indirect consequence of the inhibitory effect of D-mannose on glycolysis [83]. Mechanistically, D-mannose promotes transforming growth factor (TGF)-β production, which is mediated at least in part through ROS produced by increased FAO, an indirect consequence of the inhibitory effect of D-mannose on glycolysis [83].…”