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

Nat Commun. 2020 May 11;11(1):2331. doi: 10.1038/s41467-020-16241-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Candida albicans / metabolism
  • Candida albicans / ultrastructure
  • Down-Regulation
  • Dynamic Light Scattering
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Immunomodulation*
  • Inflammation / pathology
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Macrophage-1 Antigen / metabolism*
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Models, Biological
  • Monocytes / metabolism*
  • Monocytes / microbiology
  • Monocytes / ultrastructure
  • Protein Transport
  • Solubility
  • Transcription, Genetic
  • Transforming Growth Factor beta1 / metabolism*
  • Transport Vesicles / metabolism*
  • Up-Regulation
  • beta-Glucans / metabolism

Substances

  • Interleukin-6
  • Macrophage-1 Antigen
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • beta-Glucans