Abstract
Uncontrolled endoplasmic reticulum (ER) stress responses are proposed to contribute to the pathology of chronic inflammatory diseases such as type 2 diabetes or atherosclerosis. However, the connection between ER stress and inflammation remains largely unexplored. Here, we show that ER stress causes activation of the NLRP3 inflammasome, with subsequent release of the pro-inflammatory cytokine interleukin-1β. This ER-triggered proinflammatory signal shares the same requirement for reactive oxygen species production and potassium efflux compared with other known NLRP3 inflammasome activators, but is independent of the classical unfolded protein response (UPR). We thus propose that the NLRP3 inflammasome senses and responds to ER stress downstream of a previously uncharacterized ER stress response signaling pathway distinct from the UPR, thus providing mechanistic insight to the link between ER stress and chronic inflammatory diseases.
Highlights
Recent years have seen remarkable growth in our understanding of the cellular and molecular mechanisms that control the inflammatory response
The presence of processed IL-1b was detected in the supernatant of the human monocytic cell line THP-1 and primary human monocytes – macrophages following stimulation with tunicamycin (Figures 1a and b)
The NLRP3 inflammasome is composed of NLRP3, Cardinal, the adaptor ASC and caspase-1, and mediates the production of active IL-1b in response to an ever-expanding list of stimuli.[4]
Summary
Recent years have seen remarkable growth in our understanding of the cellular and molecular mechanisms that control the inflammatory response. As the mechanism by which ER stress triggers inflammation remains poorly understood, we sought to investigate the role of the NLRP3 inflammasome as a potential sensor of ER stress
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