Abstract
Exosomes are membranous nanovesicles released by most cell types from multi-vesicular endosomes. They are speculated to transfer molecules to neighboring or distant cells and modulate many physiological and pathological procedures. Exosomes released from the gastrointestinal epithelium to the basolateral side have been implicated in antigen presentation. Here, we report that luminal release of exosomes from the biliary and intestinal epithelium is increased following infection by the protozoan parasite Cryptosporidium parvum. Release of exosomes involves activation of TLR4/IKK2 signaling through promoting the SNAP23-associated vesicular exocytotic process. Downregulation of let-7 family miRNAs by activation of TLR4 signaling increases SNAP23 expression, coordinating exosome release in response to C. parvum infection. Intriguingly, exosomes carry antimicrobial peptides of epithelial cell origin, including cathelicidin-37 and beta-defensin 2. Activation of TLR4 signaling enhances exosomal shuttle of epithelial antimicrobial peptides. Exposure of C. parvum sporozoites to released exosomes decreases their viability and infectivity both in vitro and ex vivo. Direct binding to the C. parvum sporozoite surface is required for the anti-C. parvum activity of released exosomes. Biliary epithelial cells also increase exosomal release and display exosome-associated anti-C. parvum activity following LPS stimulation. Our data indicate that TLR4 signaling regulates luminal exosome release and shuttling of antimicrobial peptides from the gastrointestinal epithelium, revealing a new arm of mucosal immunity relevant to antimicrobial defense.
Highlights
Eukaryotic cells release membrane vesicles into their extracellular environment under physiological and pathological conditions [1]
One of the major findings of this study is that activation of Toll-like receptor 4 (TLR4) signaling increases luminal release of exosomes from the biliary epithelium during C. parvum infection
Whereas a basal level of exosomal luminal release exists in cultured biliary epithelial monolayers and in the murine biliary tract, a TLR4-dependent increase in luminal release of epithelial exosomes was detected following C. parvum infection
Summary
Eukaryotic cells release membrane vesicles into their extracellular environment under physiological and pathological conditions [1]. These vesicles mediate the secretion of a wide variety of proteins, lipids, mRNAs, and microRNAs (miRNAs), interact with neighboring cells, and thereby traffic molecules from the cytoplasm and membranes of one cell to other cells or extracellular spaces [1,2]. Exosomes do not contain a random array of intracellular proteins, but a specific set of protein families arising from the plasma membrane, the endocytic pathway, and the cytosol, especially those of endosomal origin, such as CD63, ICAM-1, and MHC molecules [2,9,10,11,12,13]
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