| dc.description.abstract | Released in response to cellular activation, microvesicles are a major vector
mechanism for the delivery of protein, nucleic acid and bioactive lipid payloads
in local tissues and plasma. Large numbers of microvesicles (including those
from neutrophils) are found within inflammatory sites, such as the rheumatoid
synovium. Human neutrophil microvesicles promote tissue protection, and in
some cases repair, by affecting function and phenotype of other inflammatory cells.
Of these, tissue macrophages are central to the recovery of homeostasis
after an inflammatory insult.
The data herein indicate that microvesicles released by activated neutrophils
impede lipopolysaccharide and interferon gamma-induced \M1-like"
polarisation of macrophages via phosphatidylserine (PtdSer) exposure, and induce
annexin A1-dependent release of transforming growth factor beta (TGFb).
Macrophages treated with these vesicles stimulate the production of cartilage
matrix from chondrocytes, and are unable to induce an inflammatory phenotype
in fi broblasts. The efficacy of these vesicles is reproduced in two in
vivo models of acute inflammation, zymosan-induced peritonits and K/BxN
serum-transfer arthritis.
Finally, the possibility of using both autologous, and cell-line-derived microvesicles
as pharmacodynamic tools is explored. Microvesicles generated
from neutrophils from patients with rheumatoid arthritis are found to be
protective, and can outcompete the pro-inflammatory effects of both platelet
microvesicles, and those isolated from synovial
fluid of patients with rheumatoid
arthritis. By building on the observation that anxA1 on microvesicles
stimulates TGFb release in macrophages, a cell line was transfected to release
anxA1+ microvesicles, and their e ects compared to those of their wild type
counterparts. | en_US |
