Infosomes as Inflammatory Mediators: Proteomic Profiling of Proteins Enriched in Inflammatory Extracellular Vesicles

TL;DR

This study shows that NLRP3 inflammasome activation in macrophages leads to the release of inflammatory extracellular vesicles called 'infosomes', which carry specific proteins and amplify inflammation in other cells.

Contribution

The study identifies and characterizes 'infosomes' as a novel type of inflammatory extracellular vesicle generated by NLRP3 inflammasome activation.

Findings

NLRP3 inflammasome activation increases the secretion of inflammatory extracellular vesicles (infosomes).

Infosomes are enriched with proteins related to immunity, neurodegeneration, and extracellular vesicle transport.

Infosomes induce inflammatory responses in macrophages and endothelial cells.

Abstract

Extracellular vesicles (EVs), including exosomes and microvesicles, act as transmitters of various biological signals through cell-cell communication. Although EVs derived from immune response cells have been partially studied, the characteristics of EVs mediated by NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation remain unclear. Here, we characterize inflammatory EVs, termed infosomes, derived from NLRP3 inflammasome-activated macrophages, which play a role in inducing inflammation. Proteomic analysis revealed that EV production was increased in macrophages with activated NLRP3 inflammasomes and that these EVs were enriched with marker proteins involved in metabolism, membrane structure, and cytoskeletal organization. Furthermore, significantly increased proteins were associated with signaling pathways and biological processes related to immune response, phagocytosis, endocytosis, and neurodegenerative diseases. Crucially, these alterations in EV secretion and molecular composition were dependent on NLRP3 and its subsequent inflammasome activity. Functionally, these infosomes were shown to amplify the expression of inflammatory factors in both macrophages and endothelial cells. These findings provide insights into the biological roles of infosomes, suggesting that EVs generated and loaded by NLRP3 inflammasome activation act as key biological mediators that disseminate and amplify inflammatory responses through cell-cell communication. This highlights their potential as novel biomarkers and therapeutic targets for inflammatory diseases.

•Activation of the NLRP3 inflammasome enhances infosome secretion.•Infosomes are enriched in proteins for immunity, neurodegeneration and EV transport.•Infosomes are generated in an NLRP3-dependent manner.•Infosomes induce inflammation in macrophages and endothelial cells.

Activation of the NLRP3 inflammasome enhances infosome secretion.

Infosomes are enriched in proteins for immunity, neurodegeneration and EV transport.

Infosomes are generated in an NLRP3-dependent manner.

Infosomes induce inflammation in macrophages and endothelial cells.

This study reveals that activation of the NLRP3 inflammasome triggers the release of inflammatory extracellular vesicles referred to as “infosomes”, which are characterized by a distinct protein profile and are capable of inducing inflammatory responses in recipient cells.

Figures