Inflammasome-induced extracellular vesicles harbour distinct RNA signatures and alter bystander macrophage responses.

Christina F Budden,Romina Kaiser,Paul J Hertzog,Lena Standke,Linden J Gearing,Eicke Latz

doi:10.1002/jev2.12127

Abstract

Infectious organisms and damage of cells can activate inflammasomes, which mediate tissue inflammation and adaptive immunity. These mechanisms evolved to curb the spread of microbes and to induce repair of the damaged tissue. Chronic activation of inflammasomes, however, contributes to non‐resolving inflammatory responses that lead to immuno‐pathologies. Inflammasome‐activated cells undergo an inflammatory cell death associated with the release of potent pro‐inflammatory cytokines and poorly characterized extracellular vesicles (EVs). Since inflammasome‐induced EVs could signal inflammasome pathway activation in patients with chronic inflammation and modulate bystander cell activation, we performed a systems analysis of the ribonucleic acid (RNA) content and function of two EV classes. We show that EVs released from inflammasome‐activated macrophages carry a specific RNA signature and contain interferon β (IFNβ). EV‐associated IFNβ induces an interferon signature in bystander cells and results in dampening of NLRP3 inflammasome responses. EVs could, therefore, serve as biomarkers for inflammasome activation and act to prevent systemic hyper‐inflammatory states by restricting NLRP3 activation in bystander cells.

Highlights

Inflammation is a vital response of the immune system that evolved to limit microbial infections and is necessary to repair sterile tissue damage
While tolllike receptors (TLRs) activation induces transcriptional reprogramming within cells and thereby the expression of proinflammatory cytokines and type I interferons (IFNs) (Akira et al, 2006), inflammasomes control the post-translational proteolytic activation of pro-inflammatory cytokines (interleukin-1β (IL-1β) and IL-18) and gasdermins, which together orchestrate a pro-inflammatory form of cell death, termed pyroptosis (Broz, 2019)
Since we were interested in extracellular vesicles (EVs) released upon activation of the NLRP3 inflammasome, we primed THP-1 macrophages with LPS followed by stimulation with the well-characterized NLRP3 activators nigericin or R837 (Groß et al, 2016; Mariathasan et al, 2006) (Figures 1e and S1a)

Summary

Introduction

Inflammation is a vital response of the immune system that evolved to limit microbial infections and is necessary to repair sterile tissue damage. If the immune response cannot stop the pathogen or if sterile triggers of inflammation persist, chronic, non-resolving inflammation develops and can result in inflammatory diseases. Infectious organisms, cell stress or cell damage activate germline-encoded innate immune signalling receptors, including tolllike receptors (TLRs) and inflammasomes, through microbial signature molecules or the appearance of modified or mis-localized host molecules. While TLR activation induces transcriptional reprogramming within cells and thereby the expression of proinflammatory cytokines and type I interferons (IFNs) (Akira et al, 2006), inflammasomes control the post-translational proteolytic activation of pro-inflammatory cytokines (interleukin-1β (IL-1β) and IL-18) and gasdermins, which together orchestrate a pro-inflammatory form of cell death, termed pyroptosis (Broz, 2019). In the last two decades, basic research uncovered many of

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