Immune modulation by complement receptor 3 (CD18/CD11b) dependent human monocyte TGF-β1-transporting vesicles

Extracellular vesicles play an important role in human cellular communication. Here, we show that human and mouse monocytes release TGF-β1-transporting vesicles in response to the pathogenic fungus Candida albicans. Soluble beta-glucan from Candida albicans binds to complement receptor 3 (CR3, CD11b/CD18) on monocytes and induces the release of TGF-β1-transporting vesicles. CR3-dependence is demonstrated using CR3-deficient (CD11b knockout) monocytes generated by CRISPR-CAS9 genome editing and isolated from CR3-deficient (CD11b knockout) mice. Isolated vesicles dampen the pro-inflammatory response in human M1-macrophages as well as in whole blood. Binding of the vesicle-transported TGF-β1 to the TGF-β receptor inhibits IL-1β gene transcription via the SMAD7 pathway in whole blood and induces TGF-β1 transcription in endothelial cells. Inhibition of TGF-β1 relieved the suppression of such proinflammatory effect. Notably, human opsonized apoptotic bodies induce similar TGF-β1-transporting vesicles in monocytes, suggesting that the early immune response is suppressed through this newly identified CR3-dependent anti-inflammatory vesicle pathway.