Chronic stress enhances microglia activation and exacerbates death of nigral dopaminergic neurons under conditions of inflammation

Rocío M de Pablos, Antonio J Herrera, Ana M Espinosa-Oliva, Manuel Sarmiento, Mario F Muñoz, Alberto Machado, José L Venero, Rocío M de Pablos, Antonio J Herrera, Ana M Espinosa-Oliva, Manuel Sarmiento, Mario F Muñoz, Alberto Machado, José L Venero

Abstract

Background: Parkinson's disease is an irreversible neurodegenerative disease linked to progressive movement disorders and is accompanied by an inflammatory reaction that is believed to contribute to its pathogenesis. Since sensitivity to inflammation is not the same in all brain structures, the aim of this work was to test whether physiological conditions as stress could enhance susceptibility to inflammation in the substantia nigra, where death of dopaminergic neurons takes place in Parkinson's disease.

Methods: To achieve our aim, we induced an inflammatory process in nonstressed and stressed rats (subject to a chronic variate stress) by a single intranigral injection of lipopolysaccharide, a potent proinflammogen. The effect of this treatment was evaluated on inflammatory markers as well as on neuronal and glial populations.

Results: Data showed a synergistic effect between inflammation and stress, thus resulting in higher microglial activation and expression of proinflammatory markers. More important, the higher inflammatory response seen in stressed animals was associated with a higher rate of death of dopaminergic neurons in the substantia nigra, the most characteristic feature seen in Parkinson's disease. This effect was dependent on glucocorticoids.

Conclusions: Our data demonstrate that stress sensitises midbrain microglia to further inflammatory stimulus. This suggests that stress may be an important risk factor in the degenerative processes and symptoms of Parkinson's disease.

Figures

Figure 1
Figure 1
Experimental groups and treatments. Intranigral injections of vehicle (Veh) or lipopolysaccharide (LPS) were given at day 1. In the stressed groups (S, SL and SLR), intranigral injections were carried out after the application of the first stressor (10 minutes of forced swimming). In the SLR group, RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)) was injected subcutaneously every day 1 hour before the stressor. V, vehicle; S, stress; L, lipopolysaccharide; SL, lipopolysaccharide injected into stressed animals; SLR, lipopolysaccharide injected into stressed animals treated with RU486.
Figure 2
Figure 2
Validation of the stress model. (A) Body weight gain (in grams). *P < 0.05. (B) Adrenal gland weight (in milligrams; bars) and ratio between adrenal gland weight and body weight gain (scatterplot and line). **P < 0.01, #P < 0.01 (for adrenal gland weight/body weight gain ratio). (C) Serum corticosterone (percentage of control animals). *P < 0.01 compared with control, aP < 0.01 compared with previous time point (S1d to S10d indicates days subjected to variate stress). Statistical significance was calculated by using Student’s t-test to compare data before (C) and after 10 days (S10d) of variate stress. Data were derived from one-way analysis of variance followed by the least significant difference (LSD) post hoc test for multiple range comparisons.
Figure 3
Figure 3
Effect of chronic stress on the lipopolysaccharide-induced activation of microglia in the ventral mesencephalon. Midbrain microglia were evaluated by immunohistochemistry with Iba-1 (left and middle columns) and OX-6 antibodies (right column) in vehicle-injected animals (A) through (F) and lipopolysaccharide (LPS)-injected animals (G) through (L) under nonstressed conditions ((A) through C) and (G) through (I)) and stressed conditions ((D) through (F) and (J) through (L)). Iba-1 immunohistochemistry is shown at low and high magnification (left and middle columns, respectively). (M) through (O) The effect of RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)) on the microglia population in response to LPS injection in stressed animals. Note that stress highly increased the microglial activation response to LPS injection (J) through (L) compared with nonstressed conditions (G) through (I). Note that, after LPS injection, most microglial cells display a round morphology typical of macrophages, whose density significantly increases under conditions of chronic stress. Also note how RU486 treatment strongly prevents the stress-induced sensitisation of microglia to subsequent LPS injection (M) through (O). The blue staining in all panels is the Monastral Blue inert tracer contained in the vehicle. Scale bars: 500 μm (A, D, G, J and M); 100 μm (all other panels). Abbreviations: V, Vehicle; S, Stress; SL, Lipopolysaccharide injected into stressed animals; SLR, Lipopolysaccharide injected into stressed animals treated with RU486.
Figure 4
Figure 4
Effect of lipopolysaccharide and stress on the number of activated microglial cells in the substantia nigra. Quantification of changes on the reactive microglial population in the substantia nigra at the end of the treatments. Results are mean ± SD of four independent experiments expressed as OX-6-positive cells/mm2. P < 0.001 by one-way analysis of variance followed by the least significant difference post hoc test for multiple range comparisons: a, compared with vehicle (V); b, compared with stress (S); c, compared with lipopolysaccharide (L); d, compared with stress + lipopolysaccharide (SL). SLR, Lipopolysaccharide injected into stressed animals treated with RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)).
Figure 5
Figure 5
Effect of lipopolysaccharide and stress on expression of tumour necrosis factor α, interleukin 1β, interleukin 6 and inducible nitric oxide synthase mRNAs in substantia nigra. mRNA expression was quantified by real-time RT-PCR. Stress had no effect in the vehicle-injected animals. As expected, lipopolysaccharide (LPS) injection increased the expression levels of mRNA. This induction was higher when LPS and stress were combined, whereas treatment with RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)) prevented this effect. Results are mean ± SD of at least three independent experiments expressed as percentage of control values. Statistical significance was calculated by one-way analysis of variance followed by the least significant difference post hoc test for multiple range comparisons a, compared with vehicle (V); b, compared with stress (S); c, compared with lipopolysaccharide (L); d, compared with stress + lipopolysaccharide (SL). SLR, Lipopolysaccharide injected into stressed animals treated with RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)). (A) Tumour necrosis factor α (TNF-α), P < 0.001. (B) Interleukin 1β (IL-1β), P < 0.001. (C) Interleukin 6 (IL-6), P < 0.01. (D) Inducible nitric oxide synthase (iNOS), P < 0.01.
Figure 6
Figure 6
Effect of stress and lipopolysaccharide on inhibitor of nuclear factor κB kinase, subunit β, and Iba-1 in the substantia nigra. Iba-1 immunofluorescence (A), (D) and (G) and inhibitor of nuclear factor κB kinase, subunit β (IKKβ), immunofluorescence (B), (E) and (H) show robust induction of IKKβ in Iba-1-labelled microglial cells in the merged images (C), (F) and (I). Images (A), (B) and (C) were taken of an animal injected with lipopolysaccharide (LPS; L). Images (D) through (F) were taken of a stressed animal injected with LPS (SL). Images (G), (H) and (I) are high-magnification photomicrographs showing one representative cell. Scale bars: (A) through (F), 200 μm; (G) through (I), 25 μm. Arrows indicate colocalizing cells.
Figure 7
Figure 7
Effect of stress and lipopolysaccharide on lipid peroxidation in the substantia nigra. Lipid peroxidation increased in stressed animals as well as after the injection of lipopolysaccharide (LPS) in nonstressed animals. When combined, stress and LPS had an additive effect. P < 0.01 by one-way analysis of variance followed by least significant difference post hoc test for multiple range comparisons. a, compared with vehicle (V); b, compared with stress (S); c, compared with lipopolysaccharide (L). SL, stressed animals injected with lipopolysaccharide.
Figure 8
Figure 8
Effect of stress and lipopolysaccharide on the expression of CD200, chemokine (C-X3-C motif) receptor 1 and monocyte chemoattractant protein 1 mRNAs in the substantia nigra. mRNA expression was quantified by real-time RT-PCR. (A) CD200. Lipopolysaccharide (LPS) decreased CD200 expression in nonstressed animals and increased it in stressed rats. (B) Chemokine (C-X3-C motif) receptor 1 (CX3CR1). LPS decreased CX3CR1expression in nonstressed animals, and in stressed animals the decrease was even greater. (C) Monocyte chemoattractant protein 1 (MCP-1). No significant change was observed after injection of LPS into nonstressed rats. However, the effect of LPS on MCP-1 expression in stressed animals was massive. P < 0.01 by one-way analysis of variance followed by least significant difference post hoc test for multiple range comparisons. a, compared with vehicle (V); b, compared with lipopolysaccharide (L). SL, stressed animals injected with lipopolysaccharide.
Figure 9
Figure 9
Effect of stress and lipopolysaccharide in astroglia in the substantia nigra. (A) Coronal section showing glial fibrillary acidic protein (GFAP) immunoreactivity in a vehicle-injected nonstressed animal (arrow points to injection site). A limited alteration restricted to the needle tract is observed. (B) High-magnification image of the area within the box in (A). (C) GFAP immunoreactivity in a lipopolysaccharide (LPS)-injected nonstressed animal. There is an area lacking GFAP immunoreactivity around the injection track (dotted encircled area). (D) High-magnification image of the square box in (C); the arrow shows the injection site. (E) GFAP immunoreactivity in a LPS-injected stressed animal. The area lacking GFAP immunoreactivity is bigger (dotted encircled area). (F) High magnification of the square box in panel E showing hypertrophic astrocytes surrounding the injection site. Scale bars: (A), (C) and (E), 500 μm; (B), (D) and (F), 100 μm. Abbreviations: V, vehicle; S, stress; L, lipopolysaccharide; SL, lipopolysaccharide injected into stressed animals; SLR, lipopolysaccharide injected into stressed animals treated with RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)). (G) Quantification of the areas lacking GFAP immunoreactivity on the substantia nigra at the end of the treatments. Results are mean ± SD of at least four independent experiments expressed in millimetres squared. P < 0.001 by analysis of variance followed by least significant difference post hoc test for multiple comparisons. a, compared with vehicle (V); b, compared with stress (S); c, compared with lipopolysaccharide (L). SL, stressed animals injected with lipopolysaccharide; SLR, lipopolysaccharide injected into stressed animals treated with RU486.
Figure 10
Figure 10
Chronic stress increases the lipopolysaccharide-induced loss of dopaminergic neurons in the substantia nigra. (A) Coronal section showing tyrosine hydroxylase (TH) immunoreactivity after the injection of vehicle (arrow) in nonstressed animals. (B) TH immunoreactivity after the injection of vehicle (arrow) in stressed animals. No significant changes can be observed. (C) TH immunoreactivity after the injection of 2 μg of lipopolysaccharide (LPS) into the substantia nigra (SN) of nonstressed rats. There is a loss of dopaminergic neurons around the injection track (arrow). (D) TH immunoreactivity after the injection of 2 μg of LPS into the SN of stressed rats. The loss of neurons is higher around the injection track (arrow). (E) RU486 (mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)) diminished the loss of TH-positive neurons caused by the combined action of LPS and stress. Scale bar: 500 μm. Abbreviations: V, vehicle; S, stress; L, lipopolysaccharide; SL, lipopolysaccharide injected into stressed animals; SLR, lipopolysaccharide injected into stressed animals treated with RU486. (F) Quantification of the number of TH-positive cells. Results are mean ± SD of four independent experiments expressed as TH-positive cells within the bounded area of the SN. P < 0.001 by analysis of variance followed by least significant difference post hoc test for multiple comparisons. a, compared with V; b, compared with S; c, compared with L; d, compared with SL. (G) Immunofluorescence of TH after the injection of 2 μg of LPS into the SN of stressed rats. (H) Immunofluorescence of Iba-1 after the injection of 2 μg of LPS into the SN of stressed rats. (I) Merged image of (G) and (H) showing activated microglia around the dopaminergic neurons. Scale bars in (G) through (I): 100 μm.

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