Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization

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Abstract

Background

Neuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson’s disease. Here, we investigated mild ER stress-based regulation of lipopolysaccharide (LPS)-driven neuroinflammation in rats and in primary microglia.

Methods

Male Sprague–Dawley (SD) rats received the intracerebroventricular injection of the ER stress activator tunicamycin (TM) with or without intraperitoneal injection of the ER stress stabilizer sodium 4-phenylbutyrate (4-PBA) 1 h before LPS administration. The levels of neuroinflammation and memory dysfunction were assessed 24 h after treatment. In addition, the effect of mild ER stress on microglia was determined in vitro.

Results

Here, we found that low doses of TM led to mild ER stress without cell or organism lethality. We showed that mild ER stress preconditioning reduced microglia activation and neuronal death as well as improved LPS-induced memory impairment in rats. In addition, pre-exposure to nonlethal doses of TM in microglia showed significant protection against LPS-induced proinflammatory cytokine production and M1/2b polarization. However, sodium 4-PBA, a compound that ameliorates ER stress, ablated this protective effect in vivo and in vitro.

Conclusions

Based on our findings, we conclude that the mild ER stress not only limits the accumulation of misfolded proteins but also protects tissues from harmful endotoxemia insults. Therefore, ER stress preconditioning has potential therapeutic value for the treatment of neurodegenerative diseases.

Electronic supplementary material

The online version of this article (10.1186/s12974-017-1002-7) contains supplementary material, which is available to authorized users.

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Most cited references 32

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Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

Liya Qin, Xuefei Wu, Michelle L. Block … (2007)

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease. (c) 2007 Wiley-Liss, Inc.

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Hormesis defined.

Mark Mattson (2008)

Hormesis is a term used by toxicologists to refer to a biphasic dose-response to an environmental agent characterized by a low dose stimulation or beneficial effect and a high dose inhibitory or toxic effect. In the fields of biology and medicine hormesis is defined as an adaptive response of cells and organisms to a moderate (usually intermittent) stress. Examples include ischemic preconditioning, exercise, dietary energy restriction and exposures to low doses of certain phytochemicals. Recent findings have elucidated the cellular signaling pathways and molecular mechanisms that mediate hormetic responses which typically involve enzymes such as kinases and deacetylases, and transcription factors such as Nrf-2 and NF-kappaB. As a result, cells increase their production of cytoprotective and restorative proteins including growth factors, phase 2 and antioxidant enzymes, and protein chaperones. A better understanding of hormesis mechanisms at the cellular and molecular levels is leading to and to novel approaches for the prevention and treatment of many different diseases.

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Is Open Access

The impact of the unfolded protein response on human disease

Shiyu Wang, Randal Kaufman (2012)

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

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Author and article information

Contributors

Yan-ning Qian:

ORCID: http://orcid.org/0000-0003-2839-2627

+86 25 8371 8836 , yanning_qian@163.com

Journal

Journal ID (nlm-ta): J Neuroinflammation

Journal ID (iso-abbrev): J Neuroinflammation

Title: Journal of Neuroinflammation

Publisher: BioMed Central (London )

ISSN (Electronic): 1742-2094

Publication date (Electronic): 28 November 2017

Publication date PMC-release: 28 November 2017

Publication date Collection: 2017

Volume: 14

Electronic Location Identifier: 233

Affiliations

[1 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Department of Anesthesiology, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu 210029 People’s Republic of China

[2 ]ISNI 0000 0004 0368 8293, GRID grid.16821.3c, Department of Anesthesiology, Shanghai General Hospital, , Shanghai Jiao Tong University School of Medicine, ; Shanghai, 200080 People’s Republic of China

Author information

Yan-ning Qian http://orcid.org/0000-0003-2839-2627

Article

Publisher ID: 1002

DOI: 10.1186/s12974-017-1002-7

PMC ID: 5704515

PubMed ID: 29179727

SO-VID: 6e961133-a5ee-467e-b2a7-5c712f0266ea

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 9 August 2017

Date accepted : 14 November 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81270429

Award ID: 81471410

Custom metadata

ScienceOpen disciplines: Neurosciences

Keywords: endoplasmic reticulum stress,neuroinflammation,microglia,neurodegeneration,lipopolysaccharide

Data availability:

ScienceOpen disciplines: Neurosciences

Keywords: endoplasmic reticulum stress, neuroinflammation, microglia, neurodegeneration, lipopolysaccharide

Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization

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Most cited references 32

Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration.

Hormesis defined.

The impact of the unfolded protein response on human disease

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