Invited review: The role of the blood-milk barrier and its manipulation for the efficacy of the mammary immune response and milk production

of newborns in all mammalian species. The composition differs considerably among species as well as the duration of lactation to satisfy the specific nutrient requirements of the offspring (Oftedal, 2020). The characteristic high concentrations of milk proteins, lactose, and potassium, and low concentrations of sodium and chloride, plasma proteins, antibodies, and leukocytes in milk from cows compared with blood can only be achieved with an intact (i.e., semipermeable) blood- milk barrier (BMB). This barrier is necessary on the The intact blood-milk barrier (BMB) prevents an uncontrolled exchange of soluble and cellular components between blood and milk in the mammary gland. It enables the sustainability of the optimal milk composition for the nourishment of the offspring. Endothelial cells, connective tissue, the basal membrane, and mainly the epithelial cells provide the semipermeability of this barrier, allowing only a selective transfer of components necessary for milk production. The epithelial cells are closely connected to each other by different formations, in which the tight junctions are the most critical for separating the milk-containing compartments from the surrounding extracellular fluid and vasculature. During mastitis, the integrity of the BMB is reduced. This facilitates the transfer of immune cells and immune factors such as antibodies from blood into milk. Simultaneously, the transfer of soluble blood constituents without an obvious immune function into milk is promoted. Furthermore, a reduced BMB integrity causes a loss of milk constituents into the blood circulation. Different mechanisms are responsible for the barrier impairment including tight junction opening, but also cell degradation. To promote the cure of mastitis, the targeted manipulation of the BMB permeability may be a tool to optimize the immune function of the mammary gland. An intensified opening of the BMB supports the antibody transfer from blood into milk, which is supposed to increase the contribution of the specific immune system in the immune defense. On the contrary, a fast closure of the BMB during the recovery from mastitis can accelerate the normalization of milk composition and milk yield. Various agents have been experimentally shown to either open (e.g., pathogens and pathogen-associated molecular patterns, several nonsteroidal anti-inflammatory drugs, oxytocin, calcium chelators) or close (e.g., glucocorticoids, nonsteroidal anti-inflammatory drugs, natural antiinflammatory drugs) the BMB.