Heat-Shock Proteins in Neuroinflammation

Abstract

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.

Keywords: diseases of the central nervous system; extracellular heat shock proteins; heat shock proteins; heat shock response; inflammation modulation; neuroinflammation.

Figure 1

The role of microglia in acute and chronic inflammations. (A) Under normal circumstances, the brain tissue is constantly monitored by resting microglia cells (1). Acute brain damage triggers dynamic microglia activation. This is a linear process that will decline over time (2). First, an early phagocytic phenotype accumulates in the injured area and begins to remove the debris (3). However, the majority of microglia rapidly converts to a pro-inflammatory phenotype via classical activation, which is neurotoxic, induces apoptosis and exacerbates inflammatory processes (4). At the same time, some microglia get alternatively activated and exert a neuroprotective effect to counteract the pro-inflammatory processes (5). After the resolution of the inflammatory cascades, microglia return to resting state and continue the tissue surveillance (6). (B) Due to physiological aging, the basic activation state of microglia is increased (2), which is associated with elevated production of cytokines and inflammatory mediators. These so-called primed microglia cells show an elevated responsiveness (3) and potentially can be more stimulated by binding disease-associated proteins and other toxic agents (4). The over-activation results in the impairment of certain microglial functions lowering their ability to eliminate the toxic protein aggregates; however, in line with their phagocytic dysfunction, their productivity of inflammatory cytokines further increases (5). This negative correlation between the expression of pro-inflammatory cytokines and the clearance of abnormal proteins generates the vicious cycle of chronic inflammation, which is a characteristic of neurodegenerative diseases (6).

Figure 2

Diverse effects of HSPs on inflammation. The exact role of HSPs in the regulation of innate and adaptive immune responses is influenced by several factors. Transcription of HSP genes is regulated by HSF1, which normally presents in the cytosol in its inactive form bounded to HSPs. Under stress conditions, the monomeric HSF1 dissociates from HSPA/C, trimerizes, and subsequently translocates to the nucleus, where it upregulates the expression of HSPs. Moreover, HSF1 was suggested to have bi-directional effect on the expression of inflammatory factors. HSF1 was shown to inhibit the expression of TNF-α by binding to its promoter, while it was also able to activate TNF-α as part of a multiprotein complex. Similarly, HSF1 was found to bind directly to IL-6 promoter opening of the chromatin structure thereby facilitating the access of activator or repressor molecules. The newly synthesized intracellular HSPs have protective and anti-apoptotic effects. Both HSPB1 and HSPA1 were shown to inhibit the activation of NF-κB by inhibiting IKK, thereby exerting an anti-inflammatory function. At the same time, cellular stress promotes the release of HSPs into the extracellular space. Lethal stress leads to the passive secretion of HSPs from necrotic cells, which usually induce a strong pro-inflammatory activity. On the other hand, HSPs can be secreted actively even under non-lethal, mild stress conditions. Although the classical protein secretory pathways are not secreting HSPs, alternative secretory mechanisms, such as exosomal release can be the basis of their regulated export. HSPs were found in the lumen of exosomal vesicles or they can occur in a membrane-associated form. Luminal HSPs cannot interact directly with the target cells only if the vesicles “burst” outside of the cell or fuse with the cell membrane, releasing HSPs into the extracellular space or into the cytosol. HSPs presented in the membrane of extracellular vesicles can bind to various surface receptors, such as toll-like receptors, that can induce the NF-κB pathway. Moreover, by sequestering antigenic molecules, HSPs are involved in antigen presentation. On the other hand, many studies confirmed that exogenous HSPA1 and HSPB1 exert anti-inflammatory effects through yet undefined mechanism in different pathological conditions. (Reviewed in van Noort, 2008; De Maio and Vazquez, 2013; Kim and Yenari, 2013). Red arrows denote pro-inflammatory, while blue arrows denote anti- inflammatory processes.