The acute phase response and soman-induced status epilepticus: temporal, regional and cellular changes in rat brain cytokine concentrations
© Johnson and Kan; licensee BioMed Central Ltd. 2010
Received: 19 May 2010
Accepted: 22 July 2010
Published: 22 July 2010
Neuroinflammation occurs following brain injury, including soman (GD) induced status epilepticus (SE), and may contribute to loss of neural tissue and declined behavioral function. However, little is known about this important pathological process following GD exposure. Limited transcriptional information on a small number of brain-expressed inflammatory mediators has been shown following GD-induced SE and even less information on protein upregulation has been elucidated. The purpose of this study is to further characterize the regional and temporal progression of the neuroinflammatory process following acute GD-induced SE.
The protein levels of 10 cytokines was quantified using bead multiplex immunoassays in damaged brain regions (i.e., piriform cortex, hippocampus and thalamus) up to 72 hours following seizure onset. Those factors showing significant changes were then localized to neural cells using fluorescent IHC.
A significant concentration increase was observed in all injured brain regions for four acute phase response (APR) induction cytokines: interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor (TNF)-α. Increases in these APR cytokines corresponded both temporally and regionally to areas of known seizure damage and neuronal death. Neurotoxic cytokines IL-1α and IL-1β were primarily expressed by activated microglia whereas the potentially neuroprotective cytokine IL-6 was expressed by neurons and hypertrophic astrocytes.
Increases in neurotoxic cytokines likely play an active role in the progression of GD-induced SE neuropathology though the exact role that these and other cytokines play in this process require further study.
Chemical warfare nerve agents (CWNA) were developed during World War II but remain a significant threat through deployment by hostile nations or by terrorist organizations . CWNA, such as soman (pinacolyl methylphosphonofluoridate, GD), rapidly and irreversibly bind to acetylcholinesterase, causing excess acetylcholine accumulation in the central and peripheral nervous systems. GD exposure can cause intense tonic-clonic convulsions, respiratory paralysis and possibly death . Following exposure, the ensuing cholinergic crisis leads to the development of status epilepticus (SE) that can continue unabated for many hours . SE induces neuroinflammatory gliosis  and profound neuronal cell loss in the piriform cortex, hippocampus, amygdala and thalamus [5, 6]. Excitotoxic neural damage following GD exposure activates a neuroinflammatory response [7–10], which may contribute to the neuropathology.
The extent to which neuroinflammation contributes to cell loss following central nervous system (CNS) injury largely depends on many factors, such as local environment, concentration of the inflammatory mediators, the responding immune cell phenotype and the timing of their interaction with damaged neural cells [11, 12]. In severe and progressive CNS injuries, increased neuroinflammatory activity appears detrimental since anti-inflammatory treatments are successful in reducing brain pathology in animal models of CNS injury [13, 14]. Following injury, infiltrating leukocytes and activated macrophages release many inflammatory proteins, including the acute phase response (APR) inducing cytokines IL-1, IL-6 and TNF-α . Though pluripotent, cytokines such as IL-1 (α and β) and TNF-α are toxic to neural tissues in vitro [16–18] and can exacerbate experimental CNS injury in vivo [19–21].
Evidence of neuroinflammation following GD-induced SE has been shown at the level of gene transcription [7–10], though data are limited on protein upregulation [22, 23]. Therefore, the purpose of this study was to investigate the extent and maturation of the neuroinflammatory response by examining cytokine protein increases following GD exposure up to 72 hours after SE onset. Protein levels of ten cytokines were quantified using a multiplex bead immunoassay in brain tissue lysates of SE-injury susceptible regions (i.e., piriform cortex, thalamus and hippocampus). APR cytokines were markedly elevated in vulnerable brain regions and were localized to resident neural cells (i.e., neurons, astrocytes or microglia). These data are the first to show concurrent cytokine protein upregulation and cellular origin of these factors following GD-induced SE.
Adult male Sprague-Dawley rats (Charles River Laboratories, Wilmington, MA; CRL: CD[SD]-BR, 250 - 350 g) were treated with HI-6 dichloride (Walter Reed Army Institute of Research, Silver Spring, MD; 125 mg/kg, i.p.) 30 minutes prior to GD administration and with atropine methyl nitrate (AMN, Sigma-Aldrich, St. Louis, MO; 2.0 mg/kg, i.m.) 1 minute after GD administration. Vehicle control animals received HI-6, AMN and saline, while naïve animals received no injections. GD (GD-U-2323-CTF-N, purity 98.8 wt%) was diluted in saline at USAMRICD. GD (1.6 LD50 = 180 μg/kg) was administered subcutaneously in the scruff of the neck and the rat was observed for convulsive activity. This dose of GD produces within minutes  a 100% generalized convulsive seizure rate that is maintained up to 24 hours . The experimental protocol was approved by the Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996), and the Animal Welfare Act of 1966 (P.L. 89-544), as amended. The animal care program at this institute is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.
Multiplex bead array immunoassay
Experimental, vehicle control and naïve animals were deeply anesthetized with a sodium pentobarbital solution (70 mg/kg, i.p.) then euthanized by decapitation at 0.5, 1, 3, 6, 12, 24, 48 or 72 hours after onset of convulsions. Following euthanasia, piriform cortex, hippocampus and thalamus tissue was extracted and processed into lysate as previously described . Briefly, the brain regions were excised, rinsed with cold PBS and snap frozen in liquid nitrogen. The tissues were weighed and homogenized in ice-cold triple detergent lysis buffer containing a Complete™ protease inhibitor cocktail (Roche Biochemicals, Indianapolis, IN) at a ratio of 1 ml buffer to 50 mg tissue. Samples were allowed to stand at 4°C for at least 30 minutes before centrifugation at 8000 G for 5 minutes and removal of the lysate for assaying. Cytokine concentrations were quantified using a rat cytokine multiplex bead immunoassay kit containing IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-17, and TNF-α (LINCO Research, St. Charles, MO). The bead immunoassay procedure used 25 μl of sample (94 ± 8 μg protein) per well and was conducted according to the manufacturer's instructions with each individual cytokine standard curve and sample assayed in duplicate. The plate was read on a Luminex™ 100 instrument (Bio-Rad Laboratories, Hercules, CA) and analyzed with either BioRad or STaRStation software (Applied Cytometry, Sacramento, CA). The number of replicates for the experimental samples are as follows: piriform cortex, n = 6 for each time point and naïve; hippocampus, n = 6 for each time point except for naïve (n = 5), 6 hr (n = 5) and 24 hr (n = 7); thalamus, n = 5 for each time point and naïve except for 0.5 hr (n = 6), 6 hr (n = 4), 12 hr (n = 3), 24 hr (n = 6) and 48 hr (n = 6). Time matched vehicle controls (n = 3 per time point) were analyzed individually and condensed into a single vehicle control comparison group when no significant difference was found between these samples over time by analyte or brain region.
Separate from the animals used in the multiplex bead array immunoassay, experimental, vehicle control and naïve animals were deeply anesthetized, euthanized by decapitation at 12 hours after seizure onset and perfused with isotonic saline followed by 4% paraformaldehyde via cardiac puncture. Brains were immediately frozen at -20°C, cut on a Leica CM3050 S cryostat (Thermo Shandon, Inc.; Pittsburgh, PA) at 40 microns and stored in cryobuffer (30% each of glycerol, ethylene glycol and water, 10% 2 × phosphate buffer) until use. Free float fluorescent IHC labeling was conducted as previously described . Experimental and vehicle control samples had an n = 3 for each cytokine/cell type combination. The antibodies used were as follows: rabbit anti-IL-1α (1:1000; ab9875, Abcam, Cambridge, MA), rabbit anti-IL-1β (1:1000; ab9787, Abcam), rabbit anti-IL-6 (1:500; ab6672, Abcam), mouse anti-NeuN to label neurons (1:1000; MAB377, Chemicon, Temecula, CA), mouse anti-GFAP to label astrocytes (1:1000; MS-280-P, NeoMarkers, Fremont, CA), and mouse anti-cd11b to label microglia and macrophages (1:1000; CBL1512, Chemicon). Alexafluor™ fluorescent-tagged secondary and tertiary antibodies (Molecular Probes, Eugene, OR) were used for visualization. Tissue sections labeled with only secondary and tertiary antibodies were used as secondary controls. Sections were viewed and digitally captured with an Olympus BX51 microscope equipped with an Olympus DP-70 high-resolution color CCD digital camera (Opelco, Dulles, VA). An Olympus BX61 equipped with a DSU spinning disk confocal system and DP-70 CCD camera was used to confirm same cell co-localization (Opelco). Images of 40 μm tissues were acquired using a z step interval of 1 μm and analyzed using Slidebook™ software (Opelco). Publication images were compiled using Adobe Photoshop CS digital image software. Color levels and background labeling were reduced and evened using the levels tool. All input levels (0-255) were normalized in the RGB channel as follows: highlight input levels were set at the peak of the image histogram, midtone levels were set at 0.8 and shadow levels were set either at the edge of the histogram closest to 255 or at 180, whichever was greater.
Immunoassay data were evaluated by ANOVA with a post-hoc Dunnett's analysis and expressed in pg/ml. Data points calculated below the minimum detectible concentrations (MinDC) for the assays were conservatively set at -0.01 pg/ml of the MinDC for statistical analyses. Values are expressed as mean ± SEM. Differences were considered significant at the level of p ≤ 0.05.
APR cytokines significantly increase following GD induced SE
IL-1 is expressed by microglia following GD induced SE
IL-6 is expressed by neurons and astrocytes following GD induced SE
Brain damage caused by CWNA induced seizure activity can cause profound behavioral changes in animals [26, 27] and may lead to behavioral impairment and a reduced quality of life for CWNA exposure survivors . Neuroinflammation is common following many types of brain injury, including seizure activity, and may exacerbate brain pathology following GD-induced SE. Our current understanding of the neuroinflammatory process following GD exposure is limited to mRNA transcript [7–10] and protein levels of a small number of factors . Neuroinflammation has been associated with brain pathology in many CNS injury models [29–31] since many inflammatory mediators are toxic to neural cells [16, 20]. This study reveals a strong induction of innate inflammatory cytokines in brain regions vulnerable to GD-induced SE.
Here, the regional and temporal protein concentration changes of 10 cytokines were quantified following GD-induced SE. We focused on three brain regions where damage is robust following GD exposure, the piriform cortex, hippocampus and thalamus [6, 32]. The protein concentrations of four APR cytokines (IL-1α, IL-1β, IL-6 and TNF-α) significantly increase and compare favorably with previously reported mRNA data [7, 9, 10]. Transcript work in a mouse model of GD exposure  revealed results similar to those reported here for IL-1β and IL-6, though TNF-α protein peaks in the rat model precede their observed mRNA peaks in the mouse model by approximately 12 hours. These discrepancies may be due to differences in HI-6 pretreatment time (5 vs. 30 minutes prior), HI-6 concentration (50 vs. 125 mg/kg), AMN treatment (none vs. 1 minute) or species physiology (mouse vs. rat). The closest comparison to this study reported mRNA expression peaks in the piriform cortex at 2 hours for TNF-α and 6 hours for IL-1β and IL-6, between 10-18 hours before the protein peaks shown in this study . In this case, transcription of the mRNA predictably precedes translation of the protein. However, they saw no significant increases in TNF-α or IL-6 mRNA but did report a significant increase in IL-1β mRNA in the hippocampus, contrary to the protein data reported here. It is unknown why these differences occurred. However, a strong increasing trend is apparent in both the mRNA (TNF-α and IL-6) and protein data (IL-1β) that is consistent with the aforementioned transcription/translation pattern and could conceivably be resolved by more data points.
Neurons, activated microglia, and astrocytes can produce neurotoxic cytokines in the brain following CNS injury . In this study, activated microglia produce both IL-1α and β, whereas dystrophic microglia express only IL-1β. Morphologically, dystrophic microglia display characteristics that may include deramification, spheroid formation, beading along the processes and cytorrhexis . It is well established that IL-1 expression by activated microglia can lead to tissue injury following CNS damage [35, 36], but little is known about dystrophic microglia or why they might preferentially express one IL-1 isoform over the other. Dystrophic microglia only appear in progressive neurodegenerative disease states [34, 37] and may be indicative of the rapid progression of an acute pathological process in this model. Coupled with the observation that IL-1β is the major form of IL-1 that contributes to CNS damage following injury [38, 39], IL-1β expression by dystrophic microglia may represent yet another signal by an injured cell to propagate the inflammatory cascade. Though unable to localize TNF-α to specific cells, expression of this pro-inflammatory cytokine can also be detrimental to neural cells in the injury area. TNF-α does not appear to be directly neurotoxic to neurons, but expression as part of neuroinflammation greatly exacerbates excitotoxic cell death in the presence of excess glutamate , a condition that likely occurs following GD exposure . Overall, expression of TNF-α, IL-1α and IL-1β is neurotoxic, contributing to neuronal cell death, edema and blood brain barrier failure following CNS injury [18, 41, 42] and likely has a similar role following GD-induced SE.
IL-6 was expressed primarily by neurons and, to a lesser extent, by hypertrophic astrocytes in this model. IL-6 expression occurs in both cell types [43–45] and can be neuroprotective in vivo [45, 46] and in vitro . Since neurons are particularly vulnerable to GD-induced SE damage [6, 47], expression of a factor that promotes neuronal survival by inducing the expression of metallothionein I + II and granulocyte-macrophage colony-stimulating factor in macrophages , stimulates the release of nerve growth factor from astrocytes  and inhibits neutrophil infiltration  to counter neurotoxic inflammatory factors such as IL-1is not surprising. Furthermore, IL-6 expression begins the synthesis of corticotrophin and glucocorticoids , initiating an anti-inflammatory feedback loop. Expression of IL-6 predictably follows early expression of IL-1α, IL-1β and TNFα. Therefore, IL-6 expression by neurons and astrocytes may be a neuroprotective mechanism initiated following the neurotoxic expression of IL-1 in microglia.
This is the first study to show concurrent upregulation and cellular origin of APR cytokines in the piriform cortex, hippocampus and thalamus following GD-induced seizure activity. The strong induction of IL-1α, IL-1β and TNF-α suggests that a neurotoxic environment is created in the brain in response to seizure activity may be countered by IL-6 expression.
List of abbreviations
acute phase response
tumor necrosis factor
chemical warfare nerve agent
central nervous system
minimum detectible concentration
polymorphic layer of the dentate gyrus.
The authors would like to thank Thuy Dao, Andrew Koemeter-Cox, Michelle Guignet, Claire Geddes and Jennifer Peeling for their expert technical support and Dr. Wolfgang Streit, University of Florida College of Medicine, for his assistance in identifying dystrophic microglia. This work was supported by the US Army Medical Research and Materiel Command and by the Defense Threat Reduction Agency (I10001_04_RC_C and W911NF-07-D-001). The findings contained herein are the private views of the author(s) and are not to be construed as official or as reflecting the views of the US Army or Department of Defense.
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