Exosomes in Intestinal Inflammation

Abstract

Exosomes are 30-150 nm sized vesicles released by a variety of cells, and are found in most physiological compartments (feces, blood, urine, saliva, breast milk). They can contain different cargo, including nucleic acids, proteins and lipids. In Inflammatory Bowel Disease (IBD), a distinct exosome profile can be detected in blood and fecal samples. In addition, circulating exosomes can carry targets on their surface for monoclonal antibodies used as IBD therapy. This review aims to understand the exosome profile in humans and other mammals, the cargo contained in them, the effect of exosomes on the gut, and the application of exosomes in IBD therapy.

Keywords: IBD; colitis; exosomes; extracellular vesicles; inflammation.

FIGURE 1

Modulation of intestinal inflammation by intestinal epithelial cell derived exosomes. Intestinal epithelial cell derived exosomes help maintain gut immune homeostasis through secretion of Annexin A1. They induce a tolerogenic immune response by secretion of integrin, cytokines and chemokines. They also protect the gut immune barrier from bacterial invasion by secreting myeloperoxidase which creates oxidative stress against bacteria. ANXA1, Annexin A1; αvβ6, Integrin αvβ6; B. fragilis, Bacteroides fragilis; CCL20, C-C Motif Chemokine Ligand 20; DC, dendritic cell; IEC, Intestinal epithelial cells; MPO: myeloperoxidase; Th17, TGF-β, transforming growth factor β; T helper 17; Treg, regulatory T cell.

FIGURE 2

Modulation of intestinal inflammation by immune cell derived extracellular vesicles. Exosomes derived from immune cells promote anti-inflammatory responses by inducing immune tolerance and triggering regulatory T cells (Treg) activation while inhibiting T helper cells. Exosome-treated immune cells further express exosomes that encourage anti-inflammatory responses. Mature APC derived exosomes promote loss of E-cadherin, which leads to breach of barrier integrity and facilitates bacterial invasion and transmigration. These exosomes also recruit immune cells and drive a pro-inflammatory immune response. Neutrophil derived exosomes secrete myeloperoxidase and miRNAs which are taken up by intestinal epithelial cells. miR-23a and miR-155 can introduce double strand breaks and impair wound healing in degenerated colonic epithelium. In summary, depending on the parent cells, exosomes derived from immune cells can drive toward a pro-inflammatory or an anti-inflammatory response. APC, antigen presenting cell; BMDC, Bone marrow derived dendritic cell; CD, cluster of differentiation; DC, dendritic cell; EV, extracellular vesicles; FOXP3, Forkhead box protein 3; IL-10, Interleukin 10; miR, microRNA; MPO: myeloperoxidase; TGF-β, transforming growth factor β; Th17, T helper 17; Treg, regulatory T cell.

FIGURE 3

Modulation of intestinal inflammation by microbiome derived outer membrane vesicles and dietary exosomes. Exosomes and OMVs (outer membrane vesicles) through their functional components, directly or indirectly interact with gut intestinal epithelial cells (IECs). Dietary exosomes attenuate apoptosis and promote intestinal wound repair. OMVs from commensal bacteria induce the proliferation of IECs and development of the intestinal tract, and indirectly enhance barrier functions by inhibiting components of the inflammatory environment that negatively impact tight junction molecules and IECs. They also interact with immune cells and promote an anti-inflammatory immune response. On the other hand, pathogenic bacteria, though their OMVs can induce inflammation and apoptosis. They can also cause a breach in the epithelial barrier by cleaving E-cadherin. This facilitates bacterial invasion and transmigration into the intestinal tissue. DC, dendritic cell; HAP, hemagglutinin protease; IL, Interleukin; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; OMV, outer membrane vesicle, PSA: capsular polysaccharide; sRNA52320, shortRNA 52320; Treg, regulatory T cell; VesC, calcium-dependent trypsin-like serine protease; ZO-1, Zonula occludens 1.