Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in APCs

Abstract

Summary Several heat shock proteins (HSP) prime immune responses which are, in part, a result of activation of antigen presenting cells (APCs). APCs respond to these immunogenic HSPs by up-regulating co-stimulatory molecules and secreting cytokines including IL-1β. These HSP-mediated responses are central mediators in pathological conditions ranging from cancer, sterile inflammation associated with trauma and rheumatoid arthritis. We tested here the requirement of inflammasomes in the release of IL-1β by one immunogenic HSP, gp96. Our results show that murine APCs activate NLRP3 inflammasomes in response to gp96, by K+ efflux. This is shown to initiate inflammatory conditions in vivo, in the absence of additional known inflammasome activators or infection. These results document a novel mechanism by which proteins of endogenous origin, the HSPs, can modulate an inflammatory response following their release from aberrant cells.

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

“…It was previously found that gp96 could induce macrophages to secrete inflammatory cytokines 20 . Recently, gp96 was found to be able to activate the inflammasome-signaling platform in antigen presenting cells (APCs) even without additional stimuli 22 . In this study, the pro-inflammatory potential of gp96 was explored in liver failure models.…”

“…Meanwhile, extracellular gp96-peptide complexes may be taken up by antigen presenting cells (APCs), and the associated peptides can be cross-presented to MHC I molecules for CD8 + T cell activation 19 . Second, gp96 itself can prime and activate multiple immune cells and induce the secretion of inflammatory cytokines by interacting with its receptors CD91, toll like receptor(TLR)2/4 and promoting the downstream NF-κB pathway, or activating NLRP3 inflammasomes of antigen presenting cells (APCs) 13 , 20 – 22 . Recently, several lines of evidence indicate that aberrantly elevated levels of extracellular gp96 are associated with chronic inflammation and autoimmune diseases.…”

The NLRP3 inflammasome in traumatic brain injury: potential as a biomarker and therapeutic target

“…The signals most commonly investigated are damage-associated molecular pattern (DAMP) and the pathogen-associated molecular pattern molecules [36]. In response to trauma, DAMPs such as reactive oxygen species (ROS) [37], high mobility group box 1 (HMGB1) [38], extracellular matrix molecules [39], and heat shock proteins [40] are known to promote priming of the NLRP3 inflammasome through toll-like receptor (TLR) and NF-κB signaling [30]. In addition, trauma can produce a range of activating signals, including but not limited to the following: ionic changes such as potassium and chloride efflux, sodium and calcium efflux, altered calcium signaling [41][42][43][44]; the presence of extracellular ATP [45]; lysosomal destabilization [46]; and products of mitochondrial dysfunction such as mitochondrial DNA and ROS [47,48].…”

The Role of Inflammation in the Pathogenesis of Preeclampsia

“…Inflammasomes are cytosolic multiprotein complexes composed of pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and proinflammatory caspase-1 [ 74 ]. The inflammasome recognition receptor is responsible for the response to microbe-derived (viral, bacterial) pathogens: pathogen-associated molecular pattern (PAMP), the body's own cells affected by stress: stress-associated molecular pattern (SAMP), and the cells from damaged tissue: damage-associated molecular pattern (DAMP) [ 75 , 76 ]. The activated receptor leads to the consequent inflammasome self-oligomerization and caspase-1 activation [ 77 ].…”