Abstract
Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.
Highlights
Heat shock proteins (HSP) are a group of phylogenetically conserved proteins found in all prokaryotic and eukaryotic cells
An aberrant overexpression of Hsp70 protein was detected in multiple sclerosis (MS) patients following an inflammatory event or thermal stress [109]. These findings suggest that the role of Hsp70 could be contextdependent; in the central nervous system (CNS), Hsp70 could be neuroprotective, whereas in peripheral blood mononuclear cells (PBMC), it could be proinflammatory
Maturation (MHC and costimulatory molecules expression) Proinflammatory cytokine secretion triggered by Hsp70-toll-like receptor (TLR) interaction Presentation of myelin basic protein (MBP)-Hsp70 and proteolipid protein (PLP)-Hsp70 complexes by major histocompatibility complex (MHC)-I or -II molecules Generation of Hsp70-specific T cells by cross-reactivity with bacterial and endogenous Hsp70 Induction of adaptive immune responses against MBP-Hsp70 and PLP-Hsp70 complexes presented by antigen presenting cells (APC) Anti-Hsp70 humoral response Death of oligodendrocytes mediated by activation of γδ T cell cytotoxicity Immunoregulation mediated by NKG2D receptor
Summary
Heat shock proteins (HSP) are a group of phylogenetically conserved proteins found in all prokaryotic and eukaryotic cells. In MS, the immune response in the CNS leads to inflammatory and oxidative conditions that induce the overexpression of most HSP (including Hsp70) in the CNS lesions of MS patients and in the EAE animal model of the MS disease [62–65].
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