Escherichia coli-Derived Outer Membrane Vesicles Relay Inflammatory Responses to Macrophage-Derived Exosomes

Extracellular vesicles are considered to be an inflammatory factor in several acute and chronic inflammatory diseases. The present study shows that exosomes from macrophages (M phi) infected with live Escherichia coli induced secretion of proinflammatory factors by uninfected M phi. Inflammatory responses induced by exosomes derived from M phi infected with heat-inactivated E. coli or lipopolysaccharide were significantly weaker than those elicited by outer membrane vesicles (OMVs) released from live E. coli. Proteome analysis of exosomes from M phi infected with live or heat-inactivated E. coli revealed that E. coli proteins OmpA, GroL1, DegP, CirA, and FepA are candidate triggers of exosome-mediated inflammatory responses. OMVs from a cirA-deleted strain suppressed exosome-mediated inflammatory responses by uninfected M phi. The C terminus of the CirA protein (residues 158 to 633), which was relayed from E. coli-derived OMV to M phi-derived exosomes, promoted exosome-mediated inflammatory responses by uninfected M phi. These results suggest an alternative mechanism by which extracellular vesicles from E. coli OMV-elicited M phi transmit proinflammatory responses to uninfected M phi.IMPORTANCE Recently, extracellular membrane vesicles (EVs) were regarded as drivers that carry cargo such as proteins, lipids, metabolites, RNA, and DNA for intracellular signaling transduction. Mammalian cells release various types of EVs, including microvesicles shed from the plasma membrane, exosomes from endosomes, apoptotic bodies, and others. EVs have been reported to mediate inflammatory signals between mammalian cells. In addition, bacteria are also known to release EVs to carry various bacterial factors. In this study, we show that bacterial EVs lead host mammalian cells to release stimulatory EVs that enhance inflammatory responses. Our results provide a novel example that bacterial EVs transduce biological signals to mammalian EVs. Recently, extracellular membrane vesicles (EVs) were regarded as drivers that carry cargo such as proteins, lipids, metabolites, RNA, and DNA for intracellular signaling transduction. Mammalian cells release various types of EVs, including microvesicles shed from the plasma membrane, exosomes from endosomes, apoptotic bodies, and others.

Automated summary

Extracellular vesicles (EVs) released from macrophages infected with live Escherichia coli can induce inflammatory responses by uninfected macrophages. The inflammatory responses induced by EVs from macrophages infected with heat-inactivated E. coli or lipopolysaccharide are weaker compared to those induced by outer membrane vesicles (OMVs) from live E. coli. The proteins OmpA, GroL1, DegP, CirA, and FepA from E. coli are potential triggers of exosome-mediated inflammatory responses.