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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 4  |  Page : 134-140

Evidence for neuroinflammation after myocardial infarction in a mouse model


1 Department of Molecular Neurobiology, University of Groningen, Groningen, Netherlands
2 Department of Physiology, VU Medical Center, Amsterdam, Netherlands
3 Department of Vascular Surgery and Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
4 Department of Molecular Neurobiology; Department of Cardiology, University of Groningen, Groningen, Netherlands

Date of Web Publication29-Oct-2018

Correspondence Address:
Ms. Leonie Gouweleeuw
Department of Molecular Neurobiology, University of Groningen, Nijenborgh 7, 9747 AG, Groningen
Netherlands
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/hm.hm_3_18

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  Abstract 

Background: The cardiovascular system and central nervous system are known to influence each other. Accordingly, neurological changes may occur after myocardial infarction (MI), which may be mediated by neuroinflammation. We investigated tumor necrosis factor alpha (TNF-α) and microglia activation in post-MI neuroinflammation. Materials and Methods: MI or sham surgery was induced in 28 male mice. Two weeks later, we performed echocardiography and dissected the brains for the western blot on TNF-α and its receptors (n = 10) or immunohistochemical stainings for microglia, doublecortin X (DCX), and TNF-α (n = 18). Plasma was collected for the measurement of circulatory cytokines. Results: The MI mice had an average infarct size of 38% of the left ventricle, heart failure was confirmed by decreased fractional shortening and increased lung weight. Plasma cytokine levels were unaltered. In brains of MI mice, there was a higher expression of TNF-α precursor protein, with trends for higher TNF-R1 and lower TNF-R2 expression. Furthermore, MI mice had more activated microglia in the inner blade of the dentate gyrus of the hippocampus. The amount of neurogenesis measured by DCX staining was unaltered. Conclusions: Our mouse model of MI showed signs of persistent neuroinflammation as indicated by raised levels of TNF-α precursor protein and an increased number of activated microglia in the hippocampus. The extent to which these neuroinflammatory hallmarks influence central nervous system functioning remain to be determined.

Keywords: Microglia, myocardial infarction, neurogenesis, neuroinflammation, tumor necrosis factor alpha


How to cite this article:
Gouweleeuw L, Pol C, Simonides WS, de Kleijn DP, Schoemaker RG. Evidence for neuroinflammation after myocardial infarction in a mouse model. Heart Mind 2017;1:134-40

How to cite this URL:
Gouweleeuw L, Pol C, Simonides WS, de Kleijn DP, Schoemaker RG. Evidence for neuroinflammation after myocardial infarction in a mouse model. Heart Mind [serial online] 2017 [cited 2021 Apr 17];1:134-40. Available from: http://www.heartmindjournal.org/text.asp?2017/1/4/134/244372


  Introduction Top


Acute myocardial infarction (MI) evokes an inflammatory response important for healing and scar formation. This inflammatory response, however, is not restricted to the heart itself, as increased levels of circulating cytokines are observed that can last for weeks following the initial MI.[1] It has been suggested that this prolonged inflammation after MI leads to neuroinflammation, influencing the central nervous system. An increase in central nervous system cytokines can influence several processes to alter neuronal function, including apoptosis, oxidative stress, and metabolic processes.[2] Furthermore, neuroinflammation following physical injury implicated in behavioral outcomes including anxiety, depression, and cognitive impairment.[3] One of the initial cytokines upregulated after MI is tumor necrosis factor alpha (TNF-α). TNF-α is produced locally by resident cardiac mast cells.[4] Circulating levels of TNF-α are raised significantly for weeks after the MI, with a peak at 4 weeks' post-MI in rats.[5] There is accumulating evidence that TNF-α influences the permeability of the blood-brain barrier at specific locations, allowing leukocyte infiltration and inflammation in the brain, as extensively reviewed by Liu et al., 2013.[6] TNF-α was also found to be upregulated in the paraventricular nucleus (PVN) of the hypothalamus in MI rats.[7] The PVN is well known for its role in connecting peripheral sympathetic outflow to the body to oxytocin/vasopressin systems in higher brain areas, including the hippocampus and amygdala. Besides an upregulation of TNF-α, prolonged microglia activation was also found in the hypothalamus of infarcted rats, supporting a process of neuroinflammation.[8],[9],[10] Persistently, increased numbers of microglia were also found in the hippocampus of mice after cardiac ischemia-reperfusion injury; this was linked to the worse performance of the cardiac injury mice in hippocampal-dependent learning tasks.[11] In the present study, we investigated the hallmarks of inflammation and neurogenesis in several brain regions. Mice were subjected to MI and plasma cytokines were measured to detect signs of peripheral inflammation, while neuroinflammation and neurogenesis were examined using western blot and immunohistochemical staining of brain tissue.


  Materials and Methods Top


Animals

12-week-old C57Bl/6J male mice were used for this study (28 total), the brains of 10 mice were used for western blotting and the brains of the other 18 animals for immunohistochemical staining. The animals were sacrificed at 14 days' post-MI. Animals were housed individually with food and water ad libitum. All experiments complied with the Guide for care and use of laboratory animals of the National Institutes of Health (Publication no. 86-23, revised 1996) and were approved by the Institutional Animal Care and use Committee of the Vrije Universiteit University Medical Center Amsterdam.

Myocardial infarction and sacrifice

Mice were randomly assigned to either sham-surgery or MI. MI was induced by permanent ligation of the left coronary artery in isoflurane-anesthetized animals, as described earlier.[12],[13] Sham animals were anesthetized and underwent thoracotomy without induction of MI. At sacrifice 14 days later, cardiac function and dimensions were obtained by echocardiography. Cardiac perfusion with saline was performed, after which the heart, lungs, and brain were collected. Blood was collected in ethylenediaminetetraacetic acid (EDTA)-tubes. Hearts and lungs were weighed, and the left ventricle was divided into infarcted and noninfarcted area which was weighed separately. Infarct size was determined as the weight of the infarcted area of the left ventricle as a percentage of the entire left ventricle weight. The brains were either fixated in 4% paraformaldehyde or frozen in liquid nitrogen and stored at −80°C.

Western blotting

Frozen whole brain tissue was homogenized in lysis buffer (150 mM NaCl, 100 mM β-glycerophosphate, 50 mM HEPES pH 7.4, 0.2% NP-40, 50 mM sodium fluoride, 15 mM sodium pyrophosphate, 10 mM EDTA, 5 mM orthovanadate, 4 mM EGTA, 1 mM DTT, and 1 mM PMSF) to which protease and phosphatase inhibitors were added. After homogenization, samples were centrifuged at 11.000 g for 20 min at 4°C. The pellet and supernatant fractions were separated for the analysis of membrane-bound and soluble proteins, respectively. Both samples were sonicated on ice for 1 min. Protein concentration was determined using a Bradford assay and samples were diluted with homogenization buffer to a concentration of 2 μg/ml, with 20% sample buffer (300 mM Tris pH 6.8, 26% glycerol, 100 g/L DTT, 0.06% Bromophenol Blue, and 0.4% sodium dodecyl sulfate [SDS]). Protein samples of 40 μg were loaded on 10% SDS-Page gels and blotted onto polyvinylidene difluoride Blotting membranes (Millipore). Membranes were blocked in 5% nonfat milk to block aspecific binding. Blots were incubated overnight with primary antibodies against TNF-α, TNF receptor 1, or TNF receptor 2 (all antibodies from cell-signaling and used at 1:1 dilution in I-block from Thermo Fisher Scientific). B-actin was used as a housekeeping gene to control for equal loading (MP Biomedicals, 1:1,000,000). After several wash steps, blots were incubated for 1 h with an appropriate horseradish peroxidase-labeled secondary antibody. Bands were visualized with a commercially available enhanced chemiluminescence kit (Pierce Biotechnology). Pictures were taken using the Chemi Doc XRS system (Bio-Rad). Image Lab software was used for analysis of the bands (Bio-Rad).

Immunohistochemistry

Brain tissue was cryoprotected with 30% w/v sucrose solution, frozen in liquid nitrogen and stored at −80°C. Tissue was cut in 20 μm sections on a cryostat and stored in 0.01M phosphate buffered saline (PBS), pH 7.4 with 0.1% sodium azide until use. The sections were blocked with a 0.1% H2O2 solution and incubated with primary antibody against Iba-1 (Wako pure chemical industries, 1:2500) for microglia, doublecortin X (DCX, Santa Cruz, 1:1000) for immature neurons or TNF-α (Abcam, 1:1000) to detect TNF-α expression. After 3 PBS washes, sections were incubated with biotinylated secondary antibodies (either rabbit anti-goat or goat anti-rabbit, both Jackson and used at 1:500 dilution). Staining was visualized by incubation with an avidin–biotin complex kit (Vector laboratories) followed by incubation with 3,3' diaminobenzidine (Sigma) activated with hydrogen peroxide. After dehydration and mounting, pictures were taken with a Leica microscope at 100x magnification for DCX and Iba-1 staining and a ×200 magnification for the TNF-α staining. The surface area of DCX stained cells was measured using ImagePro Plus 6.0.0.26 software (Media Cybernetics, Inc., Rockville, USA). Microglia activation was measured as the number of microglia profiles per high power field, as well as an increased ratio of cell body size compared to the surface area of the processes, according to methods described by Hovens et al.,[14] using ImagePro Plus 6.0.0.26 software. TNF-α positive cells were manually counted. Brain sections from TNFα-/- mice from our breeding facility were used as a negative control.

Plasma cytokine and chemokine measurements

Mouse plasma cytokine levels of interleukin-1 (IL-1) β, IL-2, IL-6, TNF-α, interferon gamma, KC, MCP-1, MiP-1 β, and RANTES were measured using a custom made 9-plex assay using a Luminex multiplex assay (Bio-Rad). ICAM-1 was measured in a single-plex Luminex assay (Bio-Rad). The provided standard curves were used for determining cytokine and chemokine concentrations in plasma on a Bio-Plex 200 suspension array system (Bio-Rad).

Statistics

All statistical analyses were performed with SPSS for Windows version 20 (IBM SPSS Statistics for Windows, 20.0.0.2, New York, USA). Data of mice with small MI sizes (<20% of the left ventricle) were excluded from the analysis. Independent samples t-test was used to determine differences between the sham-operated and large MI group. When appropriate, Welch's correction was used in case of unequal variances. P < 0.05 was considered statistically significant. All data are presented as average ± standard error of mean.


  Results Top


Cardiac dysfunction in myocardial infarction mice

Sham-operated and MI mice were sacrificed 14 days after surgery. As a measure for cardiac function and contractility, ejection fraction, and fractional shortening were measured, respectively. MI mice showed a decreased fractional shortening compared to sham-operated mice. A summary of the heart failure data can be seen in [Table 1]. To further verify cardiac dysfunction in MI mice, heart and lung weight was determined, infarct size was measured, and fractional shortening was obtained. Increased heart weight and lung weight corrected for tibia length were apparent in MI animals, indicating cardiac hypertrophy and lung edema. Infarct size in the MI group was 38% ± 9% of the left ventricle.
Table 1: Characterization of experimental groups (mean±standard error mean)

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Plasma cytokine levels

The plasma levels of 10 cytokines and chemokines were determined in a subset of animals with a Luminex assay and shown in [Figure 1]. Plasma levels for IL-1 β could not be detected for most of the samples and have not been analyzed. The assay showed no increases in cytokine levels at 14 days' post-MI. A trend toward decreased expression may be seen for IL-6 and the chemokine KC (CXCL-1), however, these results were not statistically significant.
Figure 1: Expression levels of the cytokines and chemokines interleukin-2, interleukin-6, interferon gamma, KC, MCP, MIP-1 β, RANTES, tumor necrosis factor alpha and ICAM in sham animals (white bars) and MI animals (black bars) 14 days after MI. For the markers interleukin-2, interferon gamma, KC, MCP, MIP-1b, and ICAM n = 6 for both groups. For interleukin-6, n = 10 and n = 16 for sham and MI mice. For RANTES, n = 12 and 17 for sham and MI mice and for tumor necrosis factor alpha n = 11 and 17 for sham and MI mice. Data are shown as relative expression levels where sham animals are set to 1. Error bars represent standard error of mean

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Altered levels of tumor necrosis factor alpha and receptors in the brain

Whole brain homogenates were used to determine the expression levels of TNF-α and its receptors with western blot. The pellet fraction and supernatant fraction were analyzed separately. All expression data are corrected for the expression of β-actin. Of 6 MI mice tested, 2 mice had smaller infarcts (<10% of the left ventricle) and were excluded from analyses.

Results for the expression of TNF-α and receptors are shown in [Figure 2]. We found bands at two molecular weights for TNF-α, the precursor protein at 26 kDa and the secreted protein at 17 kDa. The 26 kDa TNF-α protein was significantly increased in mice with MI compared to sham in the pellet fraction, whereas not altered in the supernatant fraction. No significant differences in the expression of the 17 kDa TNF-α protein expression were observed. A three times higher expression of the proinflammatory TNF-R1 in the pellet fraction of the MI group was observed with unaltered expression levels in the supernatant fraction. For the TNF-R2 protein, we found no differences in expression in the pellet fraction, but the supernatant had a statistically significant decrease in the expression of TNF-R2 for MI mice.
Figure 2: Western blot results of homogenized brain tissue from sham (white bars), and MI (black bars). n = 4 per group. *= significantly different from sham, P < 0.05

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To detect brain areas expressing TNF-α, staining of brain sections was performed. TNF-α positive cells were found in the piriform cortex, prefrontal cortex (PFC), and PVN, but no positive signal was observed in the hippocampus. No positive cells were found in sections from TNF-α-/- mice. When counting the number of cells per field of focus, no differences were found between sham and MI mice. Results of the TNF-α staining are shown in [Figure 3].
Figure 3: Tumor necrosis factor alpha-alpha staining in piriform cortex, paraventricular nucleus of the hypothalamus and prefrontal cortex in sham, MI and tumor necrosis factor-alpha-/-mice

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Increase in microglia number and activation in the dentate gyrus of the hippocampus

Brain sections of sham-operated and MI mice were stained for DCX and for Iba-1 to visualize immature neurons and microglia, respectively. No difference in the expression of DCX between sham and MI animals was observed, as shown in [Figure 4]a and [Figure 4]b.
Figure 4: Results from immunohistochemical stainings for doublecourtin X (a and b) and microglia (Iba-1, c-e). (a) Doublecourtin staining for the dentate gyrus of the hippocampus (10 × 10). (c) Microglia in the inner blade of the dentate gyrus (10 × 40) * P < 0.05

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Parameters obtained from the microglia staining are presented in [Figure 4]c, [Figure 4]d, [Figure 4]e. We found a significant increase in the number of microglia in the inner blade of the dentate gyrus [Figure 4]c, [Figure 4]d. Activation of microglia, as an increase in the ratio of cell body/processes, appeared significantly higher in this area [Figure 4]e. In the outer blade of the dentate gyrus, as well as in the amygdala microglia activation may occur, however, this difference was not statistically significant (P = 0.066 and 0.133, respectively).


  Discussion Top


In this study, we investigated inflammatory changes following MI. We focused on TNF-α expression in particular, as this cytokine shows upregulation after MI,[7] and was previously found upregulated in the hypothalamus following MI.[7] Neuroinflammation in different brain areas was measured as microglia activation and TNF-α expression, while neurogenesis was obtained from DCX staining of immature neurons in the dentate gyrus of the hippocampus.

Myocardial damage and plasma cytokines

MI surgery led to an average infarct size of 38% of the left ventricle. Compared to sham animals, MI mice had significantly higher heart weight/tibia length and lung weight/tibia length. Cardiac ECHO revealed higher end-diastolic and end-systolic diameters and lower fractional shortening in MI mice. Results support MI-induced cardiac dysfunction and heart failure.

Despite the considerable cardiac damage, induction of MI in this study failed to show alterations of plasma cytokine levels, including TNF-α, 14 days after surgery. This is, however, in line with a previous study where most cytokines were unaltered compared to sham 6 or 7 days after MI in mice,[15] but does not exclude increased circulating inflammatory markers at different time points.

Tumor necrosis factor alpha

In contrast to the absence of peripheral inflammation, we did find signs of neuroinflammation 14 days after MI. First, an increased expression of the 26 kDa precursor protein of TNF-α was found in MI animals. This was accompanied by trends toward a higher TNF-R1 expression in the membrane fraction and a lower expression of TNF-R2 in the supernatant fraction. A previous study in myocardial ischemia found that TNF-α promoted cardiac damage through TNF-R1 and protected against injury through TNF-R2.[16] Similarly, in a model for traumatic brain injury, TNF-R1 promotes damage while TNF-R2 seems to serve a protective role.[17] Considering this information, a higher expression of the ligand (TNF), with a shift in receptor expression toward the pro-inflammatory R1 at the expense of the cytoprotective R2 at 14 days after MI, may indicate a chronic proinflammatory state in our model.

Immunohistochemical staining against TNF-α revealed the presence of positive cells in the piriform cortex, PVN, and PFC, but not in the hippocampus. When analyzing the staining per area, no statistically significant differences were found between sham and MI, although in the PFC about twice as many TNF-α+ cells were observed. The analysis of gene expression by RNA sequencing in PFC and hippocampus revealed changes in genes related to inflammation, including a PFC-specific signal of Nr4a1.[18] This appeared the only gene upregulated in the heart as well as in PFC in MI mice and may reflect the role of macrophages in these tissues.[19]

Microglia

The altered TNF-α signaling observed could be attributed to either a general distributed proinflammatory state or, more likely, a localized neuroinflammatory response. To explore possible localized neuroinflammation, we analyzed microglia activation in relevant brain areas. Only in the hippocampus, we found an increase in the number and activation of microglia. The hippocampus has been reported as a brain area particularly sensitive to microglia activation;[20],[21] therefore, it is not surprising that microglia activation was found specifically in this region. Microglia activation in the hippocampus after MI has been reported previously.[11],[22] Other brain regions where changes in microglia were observed following MI are the PFC[22] and PVN.[8] However, we were not able to reproduce these findings in our mouse model.

Neurogenesis

DCX staining was performed to investigate neurogenesis in our MI model. Neurogenesis was previously found to be increased in a rat model 14 days after MI,[23] while in a mouse model of cardiac ischemia-reperfusion injury neurogenesis was decreased 72-h postinjury.[11] Other studies have found increased apoptosis in the hippocampus in experimental MI models.[24],[25]

When staining for DCX as a marker for neurogenesis, we were not able to show differences in expression of this marker in MI animals compared to sham, despite an increase found in microglia activation in this region. Whether microglia activation in the hippocampus is linked to either depression or neurogenesis after MI is unclear. It has previously been mentioned that IL-1 β release from microglia contributes to decreased neurogenesis.[26] Furthermore, a previous study in surgery rats showed that microglia activation was accompanied by a decrease in DCX.[27]

Limitations

While our study yields interesting results, there are several limitations. First of all, the sample size is quite small, especially since the groups were halved to separate processing for western blot and immunohistochemistry. Further, we chose a mouse model for MI. While this is a valid model previously described in cardiovascular studies, most of the previous results concerning neuroinflammation following MI have been published in rat models, making it difficult to compare results. Finally, we only investigated signs of inflammation at 14 days' post-MI. Studies in rats showed a distinct time course of changes in plasma TNF-α. Evaluating more time points could have given us additional insight.


  Conclusions Top


In this study, we found signs of neuroinflammation 14 days after MI in mice, in the absence of altered plasma cytokine levels. TNF-α precursor protein was an elevation in brains of MI mice, which was accompanied by a trend for higher TNF-R1 expression and lower TNF-R2 expression. This suggests a shift toward a more pro-inflammatory state. However, staining for tumor necrosis factor-alpha did not give a clear answer on localization within the brain. Microglia number and activation score were specifically increased in the hippocampus but were not associated with decreased neurogenesis. More research is needed to determine whether anti-inflammatory treatment is neuroprotective in models of MI and whether this could lead to new treatment options for patients.

Acknowledgments

Many thanks to Marjan Zuidwijk, Wanda Douwenga, Jan Keijser and Vince de Hoog for their technical assistance. Authors would like to acknowledge to Dr. Elizabeth Carroll for proofreading of the manuscript.

Financial support and sponsorship

This work was in part supported by the Netherlands Heart Foundation grant NHF 2006B240.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]


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