Abstract
Chronic ER stress occurs when protein misfolding in the Endoplasmic reticulum (ER) lumen remains unresolved despite activation of the unfolded protein response. We have shown that traumatic injury such as a severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory responses are not clear. Here we show that induction of chronic ER stress leads to the release of known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells (DCs) which are then capable of polarizing naïve T cells. Our findings indicate that induction of chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in persistent systemic inflammation and adverse outcomes.
Highlights
The endoplasmic reticulum (ER) is the site of secretory and membrane-bound protein synthesis
We previously demonstrated that Endoplasmic reticulum (ER) calcium store depletion is a central mediator of post-burn hepatic ER stress (Jeschke et al, 2009)
We hypothesized that ER stress may lead to the release of aggregated proteins and/or extracellular vesicles into the media which could function as damage-associated molecular patterns (DAMPs)
Summary
The endoplasmic reticulum (ER) is the site of secretory and membrane-bound protein synthesis. The presence of an excess of misfolded proteins in the ER results in the activation of ER stress signaling pathways to restore homeostasis (Almanza et al, 2019). ER chaperone content is increased while global protein synthesis rates are decreased in an effort to resolve the folding stress. If ER luminal protein folding stress cannot be resolved, pro-apoptotic pathways are activated resulting in cell death (Sano and Reed, 2013; Sovolyova et al, 2014). Chronic ER stress is characterized by activation of this pathway without significant cell death resulting in cellular and organ dysfunction over extended time periods (Oakes and Papa, 2015). We previously found that chronic ER stress is prominent post-burn injury and persists for an extended period after the initial insult
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