Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles
Luke D. Halder, Emeraldo A.H. Jo, M.Z. Hasan, Marta Ferreira‐Gomes, Thomas Krüger, Martin Westermann, Diana I. Palme, Günter Rambach, Niklas Beyersdorf, Cornelia Speth, Ilse D. Jacobsen, Olaf Kniemeyer, Berit Jungnickel, Peter F. Zipfel, Christine Skerka
Abstract
Extracellular vesicles have an important function in cellular communication. Here, we show that human and mouse monocytes release TGF-β1-transporting vesicles in response to the pathogenic fungus Candida albicans. Soluble β-glucan from C. albicans binds to complement receptor 3 (CR3, also known as 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. These vesicles reduce 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 IL1B transcription via the SMAD7 pathway in whole blood and induces TGFB1 transcription in endothelial cells, which is resolved upon TGF-β1 inhibition. Notably, human complement-opsonized apoptotic bodies induce production of similar TGF-β1-transporting vesicles in monocytes, suggesting that the early immune response might be suppressed through this CR3-dependent anti-inflammatory vesicle pathway.