Brigitta Dukay, Bálint Csoboz and Melinda E. Tóth.
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary, 2 Doctoral School in Biology, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary
The heat-shock response, one of the main pro-survival mechanisms of a living organism, has evolved as the biochemical response of cells to cope with heat stress. The most well-characterized aspect of the heat-shock response is the accumulation of a conserved set of proteins termed heat-shock proteins (HSPs). HSPs are key players in protein homeostasis acting as chaperones by aiding the folding and assembly of nascent proteins and protecting against protein aggregation. HSPs have been associated with neurological diseases in the context of their chaperone activity, as they were found to suppress the aggregation of misfolded toxic proteins. In recent times, HSPs have proven to have functions apart from the classical molecular chaperoning in that they play a role in a wider scale of neurological disorders by modulating neuronal survival, inflammation, and disease-specific signaling processes. HSPs are gaining importance based on their ability to fine-tune inflammation and act as immune modulators in various bodily fluids. However, their effect on neuroinflammation processes is not yet fully understood. In this review, we summarize the role of neuroinflammation in acute and chronic pathological conditions affecting the brain. Moreover, we seek to explore the existing literature on HSP-mediated inflammatory function within the central nervous system and compare the function of these proteins when they are localized intracellularly compared to being present in the extracellular milieu.
Neuroinflammation is a well-known feature of different acute brain disorders including ischemic stroke, traumatic brain injury, and chronic neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases (Kim and Yenari, 2013; Banjara and Ghosh, 2017). It is characterized by an increased level of cytokines and chemokines with concomitant activation of glial cells and the infiltration of leukocytes (Kim and Yenari, 2013).
Activation of the inflammatory cascades within these cells is mediated by specialized pattern-recognition receptors (PRRs) like toll-like receptors (TLRs) and NOD-like receptors (Banjara and Ghosh, 2017). PRRs recognize different danger signals triggering immune response. These danger signals can be external, mainly pathogen-derived molecules (pathogen-associated molecular patterns-PAMPs). On the other hand, tissue injury after ischemic stroke or during chronic neurodegenerative diseases can lead to sterile inflammation. In these conditions, the release of endogenous damage–associated molecules (danger-associated molecular pattern-DAMP) activates the inflammatory cascade (Banjara and Ghosh, 2017). DAMPs could flow out from necrotic cells or they can be secreted specifically by damaged cells to trigger the immune response to clean cell debris and initiate tissue repair (Giuliano et al., 2011).
DAMPs are very diverse regarding their origin and chemical properties. They include uric acid, extracellular ATP, mitochondrial DNA, misfolded proteins like β-amyloid (Aβ), glycoproteins, hormones, and extracellular RNA (Patel, 2018). Moreover, heat-shock proteins (HSPs) appear to be ideal DAMPs, as they are highly conserved molecules, one of the most abundant intracellular proteins whose expression is further increased upon tissue injury like thermal or oxidative stress or in response to infections. As molecular chaperones, HSPs are able to bind several peptides suggesting that they can be involved in antigen presentation. Moreover, HSPs themselves are able to trigger the inflammatory response (Giuliano et al., 2011).