Intracellular and extracellular expression of the major inducible 70kDa heat shock protein in experimental ischemia-reperfusion injury of the spinal cord

Awad, Hamdy; Suntres, Zacharias E.; Heijmans, John; Smeak, Daniel D.; Bergdall-Costell, Valerie; Christofi, Fievos L.; Magro, Cynthia M.; Oglesbee, Michael

doi:10.1016/j.expneurol.2008.03.024

Cited by 31 publications

(35 citation statements)

References 50 publications

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“…Although the concept of extracellular hsp70 as a danger signal to the immune system has previously been suggested by models of bacterial infection and tissue injury (53,54), our results are the first to show that hsp70 is released from viable virus-infected neuronal cells and that hsp70 interacts with TLR2 and -4 of a brain macrophage line to induce IFN-␤.…”

Section: Discussionmentioning

confidence: 44%

hsp70 and a Novel Axis of Type I Interferon-Dependent Antiviral Immunity in the Measles Virus-Infected Brain

Kim

Shu

Carsillo

et al. 2013

J Virol

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Section: Discussionmentioning

confidence: 44%

hsp70 and a Novel Axis of Type I Interferon-Dependent Antiviral Immunity in the Measles Virus-Infected Brain

Kim

Shu

Carsillo

et al. 2013

J Virol

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“…In previous work, infected H-2 b TG mice show enhanced transcript levels for Ed MeV but not Ed N522D virus relative to those for infected NT controls, establishing the in vivo relevance of in vitro studies showing loss of viral transcriptional responsiveness to hsp70 when the Ed N protein amino acid 522 is changed from asparagine to aspartic acid (8). The extracellular release of hsp70 in response to viral infection has been shown for parvovirus H1 (32), and the extracellular release of hsp70 in the CNS has recently been documented as part of the inflammatory responses to ischemia-reperfusion injury (2). The extracellular release of hsp70 emerges as a probable link between the virus-infected cell and the uninfected cells that are primarily responsible for initiating innate and adaptive immune responses.…”

Section: Discussionmentioning

confidence: 79%

Major Histocompatibility Complex Haplotype Determines hsp70-Dependent Protection against Measles Virus Neurovirulence

Carsillo

Traylor³

et al. 2009

J Virol

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In vitro studies show that hsp70 promotes gene expression for multiple viral families, although there are few reports on the in vivo significance of virus-hsp70 interaction. Previously we showed that hsp70-dependent stimulation of Edmonston measles virus (Ed MeV) transcription caused an increased cytopathic effect and mortality in transgenic hsp70-overexpressing C57BL/6 mice (H-2 b ). The response to MeV infection is influenced by the major histocompatibility complex haplotype; H-2 d mice are resistant to brain infection due to robust antiviral immune responses, whereas H-2 b mice are susceptible due to deficiencies in this response. We therefore tested the hypothesis that the outcome of MeV-hsp70 interaction may be dependent upon the host H-2 haplotype. The impact of selective neuronal hsp70 overexpression on Ed MeV brain infection was tested with congenic C57BL/10 H-2 d neonatal mice. In this context, hsp70 overexpression conferred complete protection against virus-induced mortality, compared to >30% mortality in nontransgenic mice. Selective depletion of T-cell populations showed that transgenic mice exhibit a diminished reliance on T cells for protection. Brain transcript analysis indicated enhanced innate immune activation and signaling through Toll-like receptors 2 and 4 at early times postinfection for transgenic infected mice relative to those for nontransgenic infected mice. Collectively, results suggest that hsp70 can enhance innate antiviral immunity through Toll-like receptor signaling, supporting a protective role for physiological responses that enhance tissue levels of hsp70 (e.g., fever), and that the H-2 haplotype determines the effectiveness of this response.The cellular stress response is characterized in part by the increased expression of heat shock proteins, particularly the major inducible 70-kDa isoform (hsp70, also known as hsp72). Numerous physiological stimuli can increase cellular levels of hsp70, including febrile temperatures that frequently accompany viral infection, and 70-kDa heat shock proteins support replication of both DNA and RNA viruses (reviewed in references 30 and 37), yet there is a paucity of studies examining the impact of elevated heat shock protein expression on the outcome of viral infection within animals.In vitro studies have shown that elevated cellular levels of hsp70 are associated with increased gene expression of the morbilliviruses measles virus (MeV) and canine distemper virus, members of the Paramyxoviridae. Selective overexpression via stable transfection or induction via transient heat shock both stimulate viral transcription and genome replication, resulting in increased viral protein expression and cytopathic effect (CPE) (9, 38, 39, 52, 53). hsp70-dependent gene expression reflects direct interaction between hsp70 and the viral nucleocapsid, which is composed of the single-stranded negative-sense genomic RNA packaged by the nucleocapsid protein (N) (40,52,53). The N-protein C terminus provides docking sites for both the viral polymerase and hsp70 (re...

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“…In spinal cord, Awad et al (2008) showed increases in intraand extracellular Hsp70 protein in a dog model of spinal cord ischemia, with correlation to severity of hind limb paraplegia. However, statistically significant increases were not reached in CSF until 9 h after aortic crossclamp.…”

Section: In Spinal Cord and Csfmentioning

confidence: 94%

“…Westerheide and Morimoto reviewed the potential for therapeutics based on small molecule targeting of HSF1, the heat shock factor (HSF) transcription factor (Westerheide and Morimoto 2005). Finally, Awad et al reported on Hsp70 in CSF in a dog model of spinal cord ischemia (Awad et al 2008). We will discuss Awad's results in detail later, but of interest was their statement that the release of intracellular Hsp70 during ischemia contributed to the modulation of inflammation by extracellular Hsp70.…”

Section: Introductionmentioning

confidence: 99%

Heat shock proteins as biomarkers for the rapid detection of brain and spinal cord ischemia: a review and comparison to other methods of detection in thoracic aneurysm repair

Hecker

McGarvey

2011

Cell Stress and Chaperones

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The heat shock proteins (HSPs) are members of highly conserved families of molecular chaperones that have multiple roles in vivo. We discuss the HSPs in general, and Hsp70 and Hsp27 in particular, and their rapid induction by severe stress in the context of tissue and organ expression in physiology and disease. We describe the current state of knowledge of the relationship and interactions between extra-and intracellular HSPs and describe mechanisms and significance of extracellular expression of HSPs. We focus on the role of the heat shock proteins as biomarkers of central nervous system (CNS) ischemia and other severe stressors and discuss recent and novel technologies for rapid measurement of proteins in vivo and ex vivo. The HSPs are compared to other proposed small molecule biomarkers for detection of CNS injury and to other methods of detecting brain and spinal cord ischemia in real time. While other biomarkers may be of use in prognosis and in design of appropriate therapies, none appears to be as rapid as the HSPs; therefore, no other measurement appears to be of use in the immediate detection of ongoing severe ischemia with the intention to immediately intervene to reduce the severity or risk of permanent damage.

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Intracellular and extracellular expression of the major inducible 70kDa heat shock protein in experimental ischemia-reperfusion injury of the spinal cord

Cited by 31 publications

References 50 publications

hsp70 and a Novel Axis of Type I Interferon-Dependent Antiviral Immunity in the Measles Virus-Infected Brain

hsp70 and a Novel Axis of Type I Interferon-Dependent Antiviral Immunity in the Measles Virus-Infected Brain

Major Histocompatibility Complex Haplotype Determines hsp70-Dependent Protection against Measles Virus Neurovirulence

Heat shock proteins as biomarkers for the rapid detection of brain and spinal cord ischemia: a review and comparison to other methods of detection in thoracic aneurysm repair

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