Aggregated and hyperstable damage-associated molecular patterns are released during ER stress to modulate immune function

Abstract

24Chronic ER stress occurs when protein misfolding in the ER lumen remains unresolved despite 25 activation of the unfolded protein response. We have shown that traumatic injury such as a 26 severe burn leads to chronic ER stress in vivo leading to systemic inflammation which can last 27 for more than a year. The mechanisms linking chronic ER stress to systemic inflammatory 28 responses is not clear. Here we show that induction of chronic ER stress leads to the release of 29 known and novel damage-associated molecular patterns (DAMPs). The secreted DAMPs are 30 aggregated and markedly protease resistant. ER stress-derived DAMPs activate dendritic cells 31 which are then capable of polarizing naïve T cells. Our findings indicate that induction of 32 chronic ER stress may lead to the release of hyperstable DAMPs into the circulation resulting in 33 persistent systemic inflammation and adverse outcomes. 34 35 Introduction 36The endoplasmic reticulum (ER) is the site of secretory and membrane-bound protein 37 synthesis. Under conditions where ER protein synthesis rates exceed the folding capacity of the 38 ER, unfolded or misfolded proteins accumulate in the ER lumen or membrane. The presence of 39 an excess of misfolded proteins in the ER results in the activation of ER stress signaling 40 pathways to restore homeostasis [1]. For example, ER chaperone content is increased while 41 global protein synthesis rates are decreased in an effort to resolve the folding stress. If ER 42 luminal protein folding stress cannot be resolved, pro-apoptotic pathways are activated resulting 43 in cell death [2, 3]. Chronic ER stress is characterized by activation of this pathway without 44 significant cell death resulting in cellular and organ dysfunction over extended time periods [4]. 45Inflammatory stimuli can lead to chronic ER stress in multiple cells and tissues [5]. For example, 46 activation of the acute phase response results in dramatic upregulation in the synthesis of 47 secretory proteins such as C-reactive protein resulting in hepatic ER stress [6, 7]. We previously 48 found that chronic ER stress is prominent post-burn injury and persists for an extended period 49 after the initial insult [8][9][10][11][12][13][14][15][16][17]. How chronic ER stress mechanistically contributes to post-burn 50 inflammation and metabolic dysfunction is still unclear. 51 NLR Family Pyrin Domain Containing 3 (NLRP3) plays a central role in regulating 52 inflammatory signaling transmitted by damage-associated molecular pattern molecules (DAMPs) 53 derived from stressed or damaged cells [18, 19]. Inflammatory DAMPs include intracellular 54 proteins such as high mobility group box 1 (HMBG1) and non-protein DAMPs such as nucleic 55 acids, both of which are released from dying/damaged cells. Inflammasome activation by 56DAMPs leads to caspase 1 activation, resulting in maturation and secretion of IL-1β and 57 downstream inflammatory responses [20, 21]. DAMP molecules are known to significantly 58 contribute to systemic inflammation and adverse o...

Circulating miRNAs Associated With ER Stress and Organ Damage in a Preclinical Model of Trauma Hemorrhagic Shock

“…THS is based on a primary induction of shock by bleeding upon which an induction of acute inflammation occurs as a secondary aseptic inflammation which is mainly induced by damage-associated molecular patterns (DAMPs) ( 14 ), but also by gut-derived bacterial translocation ( 15 ). Recently, it was anticipated that ER stress is linked to sterile inflammation due to the release of misfolded (unfolded) proteins which may activate immune responses through the release of DAMPs into the circulation ( 16 ). And, in fact, it was previously shown that severe ER stress causes the release of extracellular vesicles carrying proinflammatory DAMPs molecules ( 17 ).…”

“…And, in fact, it was previously shown that severe ER stress causes the release of extracellular vesicles carrying proinflammatory DAMPs molecules ( 17 ). Exactly how ER stress would lead to the release of DAMPs is still not clear, but it is assumed that autophagic vesicles create amphisomes that fuse to the plasma membrane to free the excess of misfolded proteins in an effort to support proteostasis recovery ( 16 ). Experimentally ( in vitro and in vivo ) ER stress is broadly induce by tunicamycin, thapsigargin, and brefeldin A ( 18 ).…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…It has also been shown that chronic ER stress can lead to inflammation. For example, ER stress has been shown to induce nuclear factor of the k light chain enhancer of B cells (NF-kB) activation (Deng et al, 2004), NLR family pyrin domain containing 3 (NLRP3) inflammasome activation (Menu et al, 2012), and DAMP secretion either freely (Andersohn et al, 2019) or packaged in extracellular vesicles (Collett et al, 2018).…”

Artesunate Restrains Maturation of Dendritic Cells and Ameliorates Heart Transplantation-Induced Acute Rejection in Mice through the PERK/ATF4/CHOP Signaling Pathway

“…Moreover, ART can regulate a variety of cell death (apoptosis, autophagy, iron hyperplasia, and necrosis) through regulating several signal transduction pathways (for example, the Wnt/ β -catenin pathway and the AMPK pathway) [ 12 , 13 ]. A previous study suggested that ER stress-derived damage-associated molecular patterns (DAMPs) activate DCs, which are then capable of polarizing naïve T cells [ 14 ]. This study hypothesized that ART can inhibit the oxidative stress caused by ischemia-reperfusion (IR) and inhibit the development and function of DCs through the ER pathway in the heart transplantation model.…”