Hsp70 regulates immune response in experimental autoimmune encephalomyelitis.

M José Mansilla,Herena Eixarch,Roland Martin,Catherine Lubetzki,Xavier Montalban,Carmen Espejo,Mireia Castillo,Vanja Tepavcevic,Carme Costa,Marie-Stéphane Aigrot

doi:10.1371/journal.pone.0105737

Abstract

Heat shock protein (Hsp)70 is one of the most important stress-inducible proteins. Intracellular Hsp70 not only mediates chaperone-cytoprotective functions but can also block multiple steps in the apoptosis pathway. In addition, Hsp70 is actively released into the extracellular milieu, thereby promoting innate and adaptive immune responses. Thus, Hsp70 may be a critical molecule in multiple sclerosis (MS) pathogenesis and a potential target in this disease due to its immunological and cytoprotective functions. To investigate the role of Hsp70 in MS pathogenesis, we examined its immune and cytoprotective roles using both in vitro and in vivo experimental procedures. We found that Hsp70.1-deficient mice were more resistant to developing experimental autoimmune encephalomyelitis (EAE) compared with their wild-type (WT) littermates, suggesting that Hsp70.1 plays a critical role in promoting an effective myelin oligodendrocyte glycoprotein (MOG)-specific T cell response. Conversely, Hsp70.1-deficient mice that developed EAE showed an increased level of autoreactive T cells to achieve the same production of cytokines compared with the WT mice. Although a neuroprotective role of HSP70 has been suggested, Hsp70.1-deficient mice that developed EAE did not exhibit increased demyelination compared with the control mice. Accordingly, Hsp70 deficiency did not influence the vulnerability to apoptosis of oligodendrocyte precursor cells (OPCs) in culture. Thus, the immunological role of Hsp70 may be relevant in EAE, and specific therapies down-regulating Hsp70 expression may be a promising approach to reduce the early autoimmune response in MS patients.

Highlights

Heat shock proteins (HSPs) are widely known as conserved cytoprotective proteins due to their function as chaperones, in which they help to properly fold newly synthesised proteins, prevent protein aggregation and degrade unstable and misfolded proteins [1,2,3,4,5]
At day 7 p.i., once the first EAE clinical symptoms were detected, the animals were randomised into two groups (n = 5 mice in each group) and were intravenously injected with either 200 ml of phosphate buffered saline (PBS) containing 2 mg/kg of a pool of four specific mouse Hsp70.1
At day 14 p.i., when the disease had already been established, the mice received a second dose of Hsp70.1 or nontargeting siRNA

Summary

Introduction

Heat shock proteins (HSPs) are widely known as conserved cytoprotective proteins due to their function as chaperones, in which they help to properly fold newly synthesised proteins, prevent protein aggregation and degrade unstable and misfolded proteins [1,2,3,4,5]. The expression of specific HSPs is induced to control cellular damage and restore cellular homeostasis [6,7,8]. Intracellular Hsp mediates chaperone-cytoprotective functions and can block multiple steps in the apoptosis pathway [10,11,12]. Multiple sclerosis (MS) is an autoimmune disorder in which activated CD4+ T cells initiate an inflammatory response in the central nervous system (CNS). This activation results in inflammation, gliosis, demyelination as well as oligodendrocyte and neuronal loss [17]. Immunomodulation and cytoprotection of specific cell populations in the CNS have been established as two key aspects of MS therapeutics. MS treatments have mainly focused on controlling the immune response due to the lack of effective neuroprotective treatments

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