Daily Science Podcast dari Michael Bruckman

d-mannose induces regulatory T cells and suppresses immunopathology

by WanJun Chen from the Mucosal Immunology Section of NIH

Funded by NIH

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 (Treg cells) in mice. In vitro, d-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-b activation, which in turn was mediated by upregulation of integrin avb8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of d-mannose may have clinical applications for immunopathology.

Notes:

• Fruits containing Mannose: cranberries, tomatoes, apples, peaches, and blueberries
• Vegetables containing mannose: green beans, cabbage, broccoli, and eggplant
• “d-mannose is a C-2 epimer of glucose and occurs naturally in many plants and fruits, especially cranberries.”
• “For example, a d-mannose supplement has been shown to be an effective therapy for congenital disorders of glycosylation type Ib2,4. It has also been used as a non-antibiotic treatment for bacterial urinary tract infection in animals5 and humans6, with a proposed mechanism of binding to the type 1 pili of enteric bacteria and thereby blocking their adhesion to uroepithelial cells7.”
• “However, it is unknown whether d-mannose has any effect on T cells and immune responses. Here we show that oral administration of d-mannose suppressed immunopathology in models of autoimmune diabetes and airway inflammation.”
• “We administered d-mannose in drinking water to BALB/cJ mice for 2 weeks,”
• “hus, as in mouse T cells, d-mannose also drove Treg cell generation in human naive CD4+ T cells via a TGF-β-dependent mechanism.”
• “TGF-β is produced as a latent form in complex with latent associated protein (LAP)28,29”
• “We next determined whether d-mannose has beneficial effects in autoimmunity, using as a type 1 diabetes model non-obese diabetic (NOD) mice, in which pathology involves Treg cell defects40. NOD mice received d-mannose in their drinking water starting at 7.5 weeks of age, when the mice are considered prediabetic, and at which point the inflammatory process has just been initiated but blood glucose levels are still within the normal range40 (Supplementary Fig. 11a). As expected, control (non-d-mannose-treated) NOD mice started to develop diabetes at about 12–13 weeks of age, and 80–90% became diabetic by the age of 23 weeks (Fig. 4a). However, most of the NOD mice supplemented with d-mannose were diabetes-free through 23 weeks of age (Fig. 4a).”
• “Moreover, treatment of NOD mice with d-mannose once they had reached prediabetic blood glucose levels of 140–160 mg/dL (Supplementary Fig. 11e) or new-onset diabetic levels of 200–230 mg/dL (refs. 41,42) (Supplementary Fig. 12a) suppressed the progression of diabetes (Fig. 4h–k, Supplementary Fig. 12b–d).”
• “We next tested d-mannose function in a model of lung airway inflammation.”
• “Indeed, we found that d-mannose treatment prevented the development of airway inflammation in the lungs, as demonstrated by considerably less infiltration of inflammatory cells and reduced mucus production in the airways compared with that in control mice (Fig. 6a,b).”
• “To investigate whether d-mannose can be effective in a clinically relevant setting, we first induced airway inflammation in the mice and then treated them with d-mannose in drinking water (Supplementary Fig. 15a). We found that d-mannose treatment significantly ameliorated airway inflammation (Fig. 6g–i).”
• “Here we have outlined a previously unrecognized ability of d-mannose, a hexose sugar, to suppress experimental type 1 diabetes and lung airway inflammation.”
• “Of note, long-term supplementation with d-mannose had no obvious side-effects in the NOD mice—a finding that might have implications for the development of a similar clinical therapy for type 1 diabetes in humans49.”
• “However, it should be noted that the reasons for the lack of an increased frequency of Treg cells among the polyclonal nontransgenic CD4+ T cells remain unknown and require further investigation.”
• “A previous study showed that a high concentration of glucose (for example, >25 mM) can activate TGF-β and may be involved in the growth of epithelial and mesenchymal cells46.”
• “Notably, we replicated and confirmed this immunoregulatory effect of d-mannose in an ovalbumin-induced airway inflammation model, which indicates broader efficacy of mannose-mediated therapeutic effects on immunopathology.”
• “The physiological level of d-mannose in the blood of humans and mice is approximately 100 μM. However, it has been reported that the amount of circulating d-mannose increases up to ninefold (from 100 to 900 μM) in mice receiving d-mannose in drinking water, with no adverse consequences49.”
• “In humans, stable serum d-mannose levels of up to 2 mM can be reached and are well tolerated, without signs of liver or renal toxicity51.”
• “Moreover, the possible connection between the consumption of fruits rich in d-mannose (for example, cranberries) and autoimmunity may be an interesting and important issue.”