Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter

Abstract

IntroductionThe important protective role of small heat-shock proteins (HSPs) in regulating cellular survival and migration, counteracting protein aggregation, preventing apoptosis, and regulating inflammation in the central nervous system is now well-recognized. Yet, their role in the neuroinflammatory disorder multiple sclerosis (MS) is largely undocumented. With the exception of alpha B-crystallin (HSPB5), little is known about the roles of small HSPs in disease. ResultsHere, we examined the expression of four small HSPs during lesion development in MS, focussing on their cellular distribution, and regional differences between white matter (WM) and grey matter (GM). It is well known that MS lesions in these areas differ markedly in their pathology, with substantially more intense blood-brain barrier damage, leukocyte infiltration and microglial activation typifying WM but not GM lesions.We analysed transcript levels and protein distribution profiles for HSPB1, HSPB6, HSPB8 and HSPB11 in MS lesions at different stages, comparing them with normal-appearing brain tissue from MS patients and non-neurological controls. During active stages of demyelination in WM, and especially the centre of chronic active MS lesions, we found significantly increased expression of HSPB1, HSPB6 and HSPB8, but not HSPB11. When induced, small HSPs were exclusively found in astrocytes but not in oligodendrocytes, microglia or neurons. Surprisingly, while the numbers of astrocytes displaying high expression of small HSPs were markedly increased in actively demyelinating lesions in WM, no such induction was observed in GM lesions. This difference was particularly obvious in leukocortical lesions covering both WM and GM areas.ConclusionsSince induction of small HSPs in astrocytes is apparently a secondary response to damage, their differential expression between WM and GM likely reflects differences in mediators that accompany demyelination in either WM or GM during MS. Our findings also suggest that during MS, cortical structures fail to benefit from the protective actions of small HSPs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0267-2) contains supplementary material, which is available to authorized users.

Heat shock proteins are differentially expressed in brain and spinal cord: implications for multiple sclerosis

“…Blocks were screened by immunostaining sections for PLP and HLA‐DR to select regions containing CWM/CGM in controls and NAWM/NAGM in MS cases to exclude blocks containing lesions. Although increased mRNA levels of HSPB1, HSPB6 and HSPB8 have been reported previously in MS brain NAWM , no differences in HSPB or HSP16.2 protein expression were found between controls and MS patients (Supporting information, Fig. ).…”

Heat shock protein expression in cerebral X‐linked adrenoleukodystrophy reveals astrocyte stress prior to myelin loss

“…Such a specific association with the early stages of lesion development is likely to reflect the presence of more specific factors in the pathogenesis of a disease . In MS, for example, HSPB5 is strongly and selectively induced in oligodendrocytes within preactive lesions, while other sHSPs only become upregulated in active lesions when myelin damage has already occurred . This clearly points to a critical role of oligodendrocyte stress in the development of MS lesions.…”

Preclinical stress originates in the rat optic nerve head during development of autoimmune optic neuritis

“…To investigate the preclinical disease pathology in more detail, we have investigated the expression of αB‐crystallin, a member of the small heat shock family of proteins, as a marker of cellular stress. Previous studies of autoimmune demyelinating diseases have reported that its expression is robustly up‐regulated both in MS (Bajramovic et al, ; Peferoen et al, ) and EAE (Chabas et al, ; Ousman et al, ). In particular, αB‐crystallin has been reported to be expressed early during MS pathology, being observed within both developing lesions (Bajramovic, Lassmann, & van Noort, ) and in the normal‐appearing white matter (Van Noort et al, ), where it may represent an early stress response.…”