Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli

Abstract

Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. Here, we demonstrate that Rab27a and Rab27b double knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by WT hematopoietic cells or administration of exosomes produced by GM-CSF expanded bone marrow cells. Additionally, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT but not miR-155−/− cells suggesting that uptake of miR-155-containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased following treatment with WT but not miR-155−/− exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.

Extracellular Vesicles: Catching the Light in Zebrafish

“…Concretely, tissue specific expression of an exosomal reporter, CD63-pHluorin, revealed that developing zebrafish embryos secrete massive amounts of exosomes in a syntenin-a dependent manner. In this context, the zebrafish model adds to the very few [15,16] in vivo studies of EV biogenesis pathways previously described in vitro [17]. These exosomes (majorly between 80-120nm in size) are secreted from the yolk syncytial layer (YSL) into the blood-stream, a conclusion further supported by in situ electron microscopic analysis of this layer.…”

Extracellular Vesicles with Possible Roles in Gut Intestinal Tract Homeostasis and IBD

“…With regard to the intestinal immune balance, the numbers of RAB27A-and RAB27B-positive immune cells increased in the colonic mucosa of patients with active ulcerative colitis (UC) compared to the healthy controls [125,126]. Double knockdown of Rab27A and Rab27B led to interference in protecting mice from T-cell-transfer-induced colitis, which authenticated the crucial role of Rab27mediated EVs in the treatment of IBD [127,128]. All these findings indicate that EV biogenesis acts as a key strategy for the diagnosis and/or therapeutic potential of EVs in IBD.…”

Extracellular vesicles in the hematopoietic microenvironment

“…While Rab27DKO mice showed no response to lipopolysaccharide, response could be restored following exposure to wild-type hematopoietic EVs, but not EVs harvested from miR-155 −/− cells, indicating that vesicle trafficking of miR-155 regulates the innate immune response. 88 …”