Journal Article

Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles

Halder, Luke D., Jacobsen, Ilse D., Skerka, Christine, Beyersdorf, Niklas, Ferreira-Gomes, Marta, Jungnickel, Berit, Jo, Emeraldo A. H., Westermann, Martin, Speth, Cornelia, Rambach, Günter, Kniemeyer, Olaf, Palme, Diana I., Zipfel, Peter F., Hasan, Mohammad Z., Krüger, Thomas

2020

Overview

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. Extracellular vesicles can carry immunoregulatory cytokines such as TGF-β. Here the authors use CD11b-deficient mice and macrophages to show that such vesicles carrying TGF-β are produced in response to Candida albicans infections and can limit the proinflammatory response partly via a positive feedback on TGF-β production by endothelial cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/21 / 13/31 / 13/51 / 14 / 14/1 / 14/19 / 14/28 / 38 / 38/77 / 38/91 / 631/250/2504/342 / 631/250/262 / 631/326/193/2545 / 64 / Animals / Apoptosis / beta-Glucans - metabolism / Biology / Blood / Brownian motion / Candida albicans / Candida albicans - metabolism / Candida albicans - ultrastructure / CD11b antigen / CD18 antigen / Cell interactions / Cellular communication / Chromatography / Complement / Complement receptor 3 / CRISPR / Cytokines / Down-Regulation / Dynamic Light Scattering / Endothelial cells / Extracellular vesicles / Fungi / Genome editing / Genomes / Glucan / Human Umbilical Vein Endothelial Cells - metabolism / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunomodulation / Immunoregulation / Infections / Inflammation / Inflammation - pathology / Inflammatory response / Interleukin 1 / Interleukin-6 - genetics / Interleukin-6 - metabolism / Macrophage-1 Antigen - metabolism / Macrophages / Macrophages - metabolism / Mice, Inbred C57BL / Microscopy / Models, Biological / Monocytes / Monocytes - metabolism / Monocytes - microbiology / Monocytes - ultrastructure / multidisciplinary / Natural products / Opsonization / Positive feedback / Protein Transport / Proteins / Receptors / Science / Science (multidisciplinary) / Smad7 protein / Solubility / Transcription / Transcription, Genetic / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b1 / Transport Vesicles - metabolism / Transportation / Up-Regulation / Vesicles / β-Glucan