CD11c+ myeloid cell exosomes regulate intestinal inflammation

Intercellular communication is critical for maintaining homeostasis in mammalian organ systems, including the gastrointestinal (GI) tract. Exosomes are small nanoscale lipid extracellular vesicles that mediate communication between a wide variety of cell types. Notably, the roles played by immune cell exosomes in regulating homeostasis and inflammation in the GI tract are largely uncharacterized. By generating novel mouse strains deficient in cell-specific exosome production, we demonstrate that specific disruption of exosome signaling via the deletion of Rab27a in myeloid cells exacerbates colitis, which is reversed through administration of dendritic cell (DC)-derived exosomes. Profiling small, non-coding RNAs within exosomes from colonic tissues revealed a distinct subset of microRNAs (miRNAs) carried by both colon- and DC-derived exosomes. Among the DC-enriched exosomal miRNAs, miR-146a was transferred from gut immune cells to myeloid and T cells through a Rab27-dependent mechanism to regulate macrophage phenotypes during colitis. Upon assessing clinical samples, RAB27A was also expressed at lower levels in a cohort of ulcerative colitis patients. Together, this work reveals an exosome-mediated regulatory mechanism underlying gut inflammation, and paves the way for potential use of exosomes containing miRNA cargo as a novel therapeutic for inflammatory bowel disease. Overall design: miRNA-sequencing of colon explant EVs and bone marrow dendritic cell EVs