Human milk extracellular vesicles target nodes in interconnected signalling pathways that enhance oral epithelial barrier function and dampen immune responses

Abstract

Maternal milk is nature's first functional food. It plays a crucial role in the development of the infant's gastrointestinal (GI) tract and the immune system. Extracellular vesicles (EVs) are a heterogeneous population of lipid bilayer enclosed vesicles released by cells for intercellular communication and are a component of milk. Recently, we discovered that human milk EVs contain a unique proteome compared to other milk components. Here, we show that physiological concentrations of milk EVs support epithelial barrier function by increasing cell migration via the p38 MAPK pathway. Additionally, milk EVs inhibit agonist‐induced activation of endosomal Toll like receptors TLR3 and TLR9. Furthermore, milk EVs directly inhibit activation of CD4+ T cells by temporarily suppressing T cell activation without inducing tolerance. We show that milk EV proteins target key hotspots of signalling networks that can modulate cellular processes in various cell types of the GI tract.

Exosomes: Potential Disease Biomarkers and New Therapeutic Targets

“…In addition, exosomes released by immature DCs have been proven to induce T cells apoptosis by promoting a tolerant immune response. These exosomes can also balance pro-inflammatory and anti-inflammatory effector T cells by inducing auxiliary T cells to differentiate into regulatory T cells [73], which could be achieved by the action exerted by exosome-transported IL-10, thus inducing a tolerance response [76].…”

“…For example, some exosomal circular RNAs (circRNAs), found in colostrum, play important biological roles through binding to their respective miRNAs, which promote vascular endothelial growth factor expression and induce proliferation and migration of small intestinal epithelial cells. Breast milk exosomes have also been shown to directly enhance gingival epithelial cell migration through p38 mitogen-activated protein kinases and cytoskeleton remodeling [76]. It has been hypothesized that breast milk extracellular vesicles are involved in the selective inhibition of toll-like receptors 3, 4 and 9 (TLR3, TLR4 and TLR9) through the transport of epidermal growth factor, and, probably, cystatin-B cathepsin inhibitor (CSTB) [76].…”

“…Breast milk exosomes have also been shown to directly enhance gingival epithelial cell migration through p38 mitogen-activated protein kinases and cytoskeleton remodeling [76]. It has been hypothesized that breast milk extracellular vesicles are involved in the selective inhibition of toll-like receptors 3, 4 and 9 (TLR3, TLR4 and TLR9) through the transport of epidermal growth factor, and, probably, cystatin-B cathepsin inhibitor (CSTB) [76]. These proteins inhibit the signaling of these receptors, thus protecting the intestinal epithelium against apoptosis and favoring tolerance to the microbiota.…”

Flood Control: How Milk-Derived Extracellular Vesicles Can Help to Improve the Intestinal Barrier Function and Break the Gut–Joint Axis in Rheumatoid Arthritis

“…Additionally, Zonneveld et al. have recently reported that human milk EVs can directly inhibit CD4+ T helper cell activation without inducing tolerance ( 100 ). In experimental arthritis studies, our research group at the Radboudumc found circumstantial evidence for this effect on T cells, as mice treated with bovine mEVs showed a marked reduction in Tbet (Th1) and RORyT (Th17) expression in splenocytes.…”

Editorial: Impact of Early Life Nutrition on Immune System Development and Related Health Outcomes in Later Life

“…Previous studies suggest antipathogenic effects of HM components and that the addition of these bioactive molecules (i.e., HMOs, lactoferrin, immunoglobulins, and milk fat globule membrane FGM, extracellular vesicles) to infant formulas may benefit child health (20,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), although the studies usually lack methodological rigor and outcomes were based on a small sample size. The studies on recombinant immunoglobulins and bioactivity in the digestive tract are limited.…”