Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy
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REVIEW
Open Access
Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy? Bodo C Melnik1*, Swen Malte John1 and Gerd Schmitz2
Abstract Epidemiological evidence confirmed that raw cow’s milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk’s atopyprotective mode of action remains elusive. This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and FcεRI expression. Boiling of milk abolishes milk’s exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow’s milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow’s milk consumption. The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding. Keywords: Atopy prevention, DNA demethylation, Exosome, FoxP3, MicroRNA, Milk, MiR-155, Regulatory T cell
Introduction Children who grow up on traditional farms are protected from atopic diseases [1]. Early-life consumption of unboiled cow’s milk has been identified as the most protective factor for the development of atopy [2-10]. Farm milk exposure has been associated with increased numbers of CD4+CD25+FoxP3+ regulatory T cells (Tregs), lower atopic sensitization and asthma in 4.5-year-old children [11]. Treg cell numbers are negatively associated with asthma and perennial IgE levels [11]. However, potential effectors of milk, which stimulate the development of Tregs remain elusive. This review provides translational evidence that milk-derived exosomal microRNAs may be the potential stimuli for thymic Treg maturation and raw milk-mediated atopy prevention. * Correspondence: [email protected] 1 Department of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Sedanstrasse 115, D-49090 Osnabrück, Germany Full list of author information is available at the end of the article
Atopic diseases are associated with reduced Treg numbers
Atopic allergy is a Th2 cell-mediated disease that involves the formation of specific IgE antibodies against innocuous environmental substances. Both naturally occurring thymus-derived and inducible Tregs of the periphery prevent allergy developme
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