Extracellular vesicles, including exosomes, have been identified in all biological fluids and rediscovered as an important part of the intercellular communication. Breast milk also contains extracellular vesicles and the proposed biological function is to enhance the antimicrobial defense in newborns. It is, however, unknown whether extracellular vesicles are still present in commercial milk and, more importantly, whether they retained their bioactivity. Here, we characterize the extracellular vesicles present in semi-skimmed cow milk available for consumers and study their effect on T cells. Extracellular vesicles from commercial milk were isolated and characterized. Milk-derived extracellular vesicles contained several immunomodulating miRNAs and membrane protein CD63, characteristics of exosomes. In contrast to RAW 267.4 derived extracellular vesicles the milk-derived extracellular vesicles were extremely stable under degrading conditions, including low pH, boiling and freezing. Milk-derived extracellular vesicles were easily taken up by murine macrophages in vitro. Furthermore, we found that they can facilitate T cell differentiation towards the pathogenic Th17 lineage. Using a (CAGA)12-luc reporter assay we showed that these extracellular vesicles carried bioactive TGF-β, and that anti-TGF-β antibodies blocked Th17 differentiation. Our findings show that commercial milk contains stable extracellular vesicles, including exosomes, and carry immunoregulatory cargo. These data suggest that the extracellular vesicles present in commercial cow milk remains intact in the gastrointestinal tract and exert an immunoregulatory effect.

The control of inflammation is strictly regulated to ensure the adequate intensity and duration of an inflammatory response, enabling the removal of the trigger factors and the restoration of the integrity of the tissues and their functions. This process is coordinated by anti-inflammatory and pro-resolving mediators that regulate the cellular and molecular events necessary to restore homeostasis, and defects in this control are associated with the development of chronic and autoimmune diseases. The TAM family of receptor tyrosine kinases-Tyro3, Axl, and MerTK-plays an essential role in efferocytosis, a key process for the resolution of inflammation. However, new studies have demonstrated that TAM receptor activation not only reduces the synthesis of pro-inflammatory mediators by different cell types in response to some stimuli but also stimulates the production of anti-inflammatory and pro-resolving molecules that control the inflammation. This review provides a comprehensive view of TAM receptor family members as important players in controlling inflammatory responses through anti-inflammatory and pro-resolving actions.

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