Inflammation modulates expression of laminin in the central nervous system following ischemic injury
© Ji and Tsirka; licensee BioMed Central Ltd. 2012
Received: 11 April 2012
Accepted: 3 July 2012
Published: 3 July 2012
Ischemic stroke induces neuronal death in the core of the infarct within a few hours and the secondary damage in the surrounding regions over a long period of time. Reduction of inflammation using pharmacological reagents has become a target of research for the treatment of stroke. Cyclooxygenase 2 (COX-2), a marker of inflammation, is induced during stroke and enhances inflammatory reactions through the release of enzymatic products, such as prostaglandin (PG) E2.
Wild-type (WT) and COX-2 knockout (COX-2KO) mice were subjected to middle cerebral artery occlusion (MCAO). Additionally, brain slices derived from these mice or brain microvascular endothelial cells (BMECs) were exposed to oxygen-glucose deprivation (OGD) conditions. The expression levels of extracellular matrix (ECM) proteins were assessed and correlated with the state of inflammation.
We found that components of the ECM, and specifically laminin, are transiently highly upregulated on endothelial cells after MCAO or OGD. This upregulation is not observed in COX-2KO mice or WT mice treated with COX-2 inhibitor, celecoxib, suggesting that COX-2 is associated with changes in the levels of laminins.
Taken together, we report that transient ECM remodeling takes place early after stroke and suggest that this increase in ECM protein expression may constitute an effort to revascularize and oxygenate the tissue.
Cerebral ischemia results in neurological disability and constitutes the third leading cause of death in the US. It has devastating consequences as it results in death of neurons at the infarct core within a few hours after the blockade of blood flow to the brain . Although re-establishment of blood flow using fibrinolytics is critical, inflammation that develops following the initial ischemic episode is a major mechanism by which cells in the penumbra degenerate , and therefore pharmacological strategies are formulated to limit this delayed phase of damage. Major mediators of inflammatory events are the members of the cyclooxygenase (COX) family. The two major COX isoforms are COX-1 and COX-2 and they catalyze the first step in the transformation of arachidonic acid to prostaglandins (PGs) and thromboxanes. In the central nervous system (CNS), COX-1 and COX-2 are expressed constitutively on neurons, whereas COX-2 is induced on microglia and astrocytes by inflammatory stimuli or injury [3, 4]. COX-2 is considered a proinflammatory mediator leading to PG synthesis . Prostaglandin E2 (PGE2) induces fever and pain, increases vascular permeability and recruit inflammatory cells to injury sites . However, evidence suggests that COX-2 is also involved in inflammation reduction/resolution [7, 8]. The COX-2 inhibitors NS398 and indomethacin have differential effects depending on their administration time: early administration during a pleurisy model suppressed inflammation, but late administration exacerbated inflammation through PGE2 and 15-deoxy-δ12,14-prostaglandin J2 (15d-PGJ2) . In a different paradigm, PGE2 reduced proinflammatory mediators release from mast cells and inflammatory cells recruitment in lungs , suppressed inducible nitric oxide synthase (iNOS) and tumor necrosis factor (TNF)α, but enhanced interleukin 10 and interleukin 13 expression in LPS-stimulated microglia [10, 11]. COX-2 also oxygenates anti-inflammatory endocannaboids  that protect against ischemic death . These studies suggest that COX-2 can drive or resolve inflammation; therefore, careful regulation of COX-2 may be important for reducing inflammation-mediated neurodegeneration [14, 15].
The extracellular matrix (ECM) of the CNS is essential for maintenance of brain homeostasis. Although its exact composition is not defined, it is thought that hyaluronan, tenascin-C, and proteoglycans are present in brain parenchyma , and fibronectin (FN) and laminin in the brain vasculature [17, 18]. Proteoglycans such as aggrecan, versican, and brevican constitute perineuronal nets majorly [19, 20], and tenascin is involved in regulation or promotion of neurite outgrowth [21–23]. Moreover, the structure of these molecules is changed in response to brain injury such as stroke [24, 25]. The ECM and secreted neurotrophic or other factors, such as vascular endothelial growth factor (VEGF) or brain-derived neurotropic factor (BDNF), are involved in neuronal reorganization and recovery in MCAO brains [24, 26–31]. Among the ECM proteins, laminin is rich primarily in the basement membranes of the endothelial cells of the blood–brain barrier (BBB) . Laminin levels have been reported to increase or decrease during CNS injury [29, 33]. Laminins are present in 16 isoforms that are composed of α, β and γ polypeptides. Different laminin isoforms have unique distribution, and are temporally and spatially regulated . Several of the laminin subunits have been shown to be expressed in the rodent brain, including α1 to 5, β1, and γ1 [35, 36], and the β3 and γ1 chains have been reported in sprouting neurons and rat astrocytes [37, 38]. Laminin α2 is localized in the basal lamina of cerebral blood vessels, and may be important for the selective filtration capability of BBB . The expression of laminin is upregulated in endothelial cells and astrocytes within 24 h following ischemia and stab wounds [40, 41].
The work described here investigated whether COX-2 can modulate ECM changes induced by ischemic injury. We focused on laminin as one abundant component of the ECM. Our results indicate that laminin levels on blood vessels are regulated by COX-2 following permanent or transient ischemia. Understanding the functional outcome and timing of laminin expression regulation by COX-2 in the progression of ischemia-induced neuronal damage could suggest a basis for potentially rationalizing drug specific interference with ischemia.
Animals and in vivo experiments
All animal procedures were approved by the Stony Brook University Institutional Animal Care and Use Committee (IACUC). Adult wild-type (C57BL6; WT) mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA). Cyclooxygenase knockout mice (COX-2KO in the C57Bl6 background) were provided by Dr SK Dey (Cincinnati Children's Hospital). Mice were bred in house at Stony Brook. For middle cerebral artery occlusion (MCAO), mice were anesthetized and underwent permanent MCAO (pMCAO) using a heat-blunted, small 6–0 siliconized monofilament (Ethicon, Somerville, NJ, USA). A fiberoptic probe was glued to the parietal bone (2 mm posterior and 5 mm lateral to bregma) and connected to a laser-Doppler flowmeter (Periflux System 5010, Perimed, Stockholm, Sweden) for continuous monitoring of cerebral blood flow in the ischemic territory center. Celecoxib (Biovision, Milpitas, CA, USA) was given at 5 mg/kg intraperitoneally (in 50 % dimethylsulfoxide (DMSO)) 30 minutes before the injury. The animals were killed at different times. The infarct area was visualized by cresyl violet and 2,3,5-triphenyltetrazolium chloride (TTC) staining.
Mice were anesthetized after surgery and perfused with saline solution, followed by 4 % paraformaldehyde (PFA) in 0.1 M phosphate buffer, pH 7.2, for tissue fixation. Brains were obtained and post fixed overnight at 4 °C in 4 % PFA. Fixed brains were stored at 4 °C in 30 % sucrose solution until they sank. Six separate series of 20 μm coronal brain sections were obtained with a cryostat. For protein preparation, mice were anesthetized and perfused with saline. Brains were sliced with Mice Brain Slicer Matrix (ASI Instruments, Warren, MI, USA) and a razor blade. The slice including the ipsilateral sides (ischemic lesion) was selected, and tissue blocks (1.0 × 1.0 × 1.0 mm3) in the lesion of ipsilateral sides and in the same area of contralateral (not ischemic) sides were collected, and stored at −70 °C until use.
Measurement of Infarct volume
To quantify the infarct volume TTC staining was used: mice were killed and perfused with saline after MCAO. The brain slices, obtained as described above, (2 mm) were incubated for 15 minutes in 2 % TTC (Sigma-Aldrich, St. Louis, MO, USA) at 37 °C, and fixed in 4 % PFA at 4 °C. TTC stains viable brain tissue dark red, whereas infarcted tissue areas remain unstained (white). To measure the TTC-negative area, serial sections from each animal were viewed in a Nikon E600 microscope, photographed and the area measured using NIS-Elements software (ImageJ). The infarct volume was calculated as sum of (area × section thickness) for each animal.
Oxygen-glucose deprivation (OGD)
Immortalized human brain microvascular endothelial cells (BMECs) were a gift from Dr M Stins at Johns Hopkins University, School of Medicine . BMECs were cultured in RPMI1640 medium, supplemented with 10 % NuSerum, 10 % fetal bovine serum (FBS), minimal essential medium (MEM) vitamins, MEM non-essential amino acids, 1 mM sodium pyruvate, 2 mM d-glutamine, 30 μg/ml endothelial growth supplement, 5 U/ml heparin, and penicillin/streptomycin at 37 °C in 5 % CO2. The cells form a monolayer connected via tight junctions that can form and model an in vitro blood–brain barrier . For in vitro ischemia, the cells were maintained in glucose-free and serum-free (OGD conditioned) medium under 1 % O2/5 % CO2 at 37 °C (Oxycycler C4, Biospherix, Redfield, NY, USA) for 3 days. Afterwards, the cells were removed from the hypoxic chamber and replaced with pre-OGD conditioned medium in a humidified aerobic incubator at 37 °C for 4 h recovery .
Immunoblotting, immunohistochemistry, and immunofluorescence
Antibodies used for immunostaining or immunoblotting
Santa Cruz Biotechnology
A gift of Dr Galanakis
Reverse transcription polymerase chain reaction (RT-PCR)
Primer sequences for reverse transcription polymerase chain reaction (RT-PCR)
Statistical significance was assessed by analysis of variance (ANOVA), followed by Student-Newman-Keuls multiple comparison tests. All analyses were performed using SPSS, V.8.0 (SPSS, Chicago, IL, USA). Values are means ± SEMs of at least three independent experiments using at least five animals per experimental procedure and mouse strain, unless otherwise indicated.
Laminin expression is transiently upregulated in wild-type, but not COX-2KO, mice after MCAO
Since laminin was the ECM protein whose levels were predominantly affected by MCAO, and given the known involvement of laminin in revascularization, we examined whether the MCAO and ECM changes also involved changes in the expression of VEGF, a factor known for mediating angiogenesis and neoangiogenesis. As shown in Additional file 2: Figure S2, the levels of VEGF were elevated in wild-type animals at 6 and 12 h post MCAO (peak at 6 h), but this increase was drastically attenuated in COX-2KO mice, suggesting that COX-2 could be involved in laminin-mediated angiogenesis .
Laminin is increased in endothelial cells after ischemic injury
The antibody used in Figures 2C and 3A,B was a pan-laminin antibody, so we sought to determine which laminin subunits are upregulated after MCAO. We used semiquantitative RT-PCR for each laminin subunit in extracts from the ipsilateral side of MCAO animals at the indicated times (Figure 3C). The analysis showed that laminins α2, β3, and γ1 were upregulated within 24 h (Figure 3C).
Pharmacological inhibitors of COX-2 modulate laminin levels after MCAO
COX-2 acts through E-prostanoid 3 (EP3) receptors to modulate ECM protein expression
As discussed earlier, in Figure 2, other ECM protein components were also increased after MCAO, and their expression correlated with increased inflammation. We evaluated the expression of markers not directly associated with the COX-2 pathway (TLR9, Mac-2, CD14) in the presence of coxib or EP antagonists, and found that their expression was also decreased when the COX-2 pathway was inhibited (Figure 5C). These results suggested that laminin and other ECM protein expression increase is associated with brain inflammation.
ECM components play regulatory roles in various cellular events [51–53], including healing/repair processes after injury . For some ECM proteins it has been reported that their expression increases in ischemia and stab wounds [40, 41], but it is not known what its contribution to the injury outcome is. Focusing on one ECM component, we report that the increase in laminin depends on COX-2 activity.
Laminin upregulation has been linked to wound healing stimulation [54, 55] and angiogenesis. In a skin wound model, application of laminin peptides increased the wound coverage and repair and was accompanied by enhanced angiogenesis. Laminins α2, β3, and γ1 are increased in brain following transient ischemic injury. These laminins have been reported to be expressed in brain [33, 38, 56]. The biological roles of laminin subtypes and trimer molecules are largely unknown, thus, information about their functions derives from the phenotype of deficient or knockout mice. Laminin α1 is involved in epiblast differentiation . Laminin α2 is expressed in basal lamina surrounding neurons and muscle . α2 deficiency causes congenital muscular dystrophy . Laminin β1 deficient mice lack basement membranes and display defects in the neuromuscular synapse . Laminin β3 is expressed on the basal lamina and ECM of all cerebral microvessels . The γ1 subunit is rapidly degraded during excitotoxicity  or ethanol-induced neurodegeneration . Although these subunits were upregulated after MCAO, it is not clear if they form a single laminin isoform or distinct heterotrimers. Moreover, it is not clear if they would act through the same receptors, integrins, dystroglycan or syndecan .
COX-2 activity enhances the production of VEGF , which in turn stimulates angiogenesis. The downstream effectors of COX-2 would be different prostaglandins such as PGI2, PGD2, PGE2, PGF2α, and thromboxane (Tx). These prostaglandins bind to the receptor with the greatest affinity: I prostanoid (IP) receptor binds PGI2, DP binds PGD2, EP binds PGE2, FP binds PGF2α, and TP binds TxA2, and they are basically G protein-coupled prostanoid receptors (GPCR) [62, 63]. Among the prostaglandins, prostaglandin E2 (PGE2) is the most widely produced prostaglandin in the body, and considered to participate in inflammation associated with redness, swelling and pain [64, 65] and has significant effects on proliferation, the apoptosis of lymphocytes and the regulation of cytokine production in T cells . PGE2 has the most known receptors with EP subtypes characterized as EP1 to EP4. Depending on the model of CNS injury, different EP receptors mediate the cellular signals. In a model of pulmonary emphysema angiogenesis was mediated by an EP2 agonist , whereas bone marrow cells expressing EP3 receptor enhanced angiogenesis during chronic inflammatory conditions . In Lewis lung carcinoma the proangiogenic microenvironment was regulated via COX-2/EP3 or EP4 signaling . In our study the effects of COX-2 on laminin expression were mediated through EP3 receptors. Our results suggest that although ECM changes are associated with the general acute inflammatory processes after MCAO, they may result from specific signaling changes. This latter hypothesis is supported by the fact that not all EP antagonists affect laminin expression, yet all affect other marker expression.
The observation that eventually laminin expression was recovered in COX-2-deficient animals at 2 days (data not shown) suggests that COX-2 deficiency delays the upregulation of the ECM protein laminin, potentially due to the release of different prostaglandins at early and late inflammatory stages and/or neuronal recovery during ischemic injury.
If the initial response of the ischemic tissue is an effort to promote neoangiogenesis to re-establish the blood flow [68, 69], our data suggest that the early inflammatory reactions may be aiding such a process. Our results also point to molecular components critical for increased vascularization, suggesting that inhibition of molecules, such as EP3, may not be beneficial for stroke outcome.
Our study shows that following MCAO a transient upregulation of proteins of the ECM is observed, primarily of proteins associated with the endothelial cells of the CNS blood vessels. The presence of COX-2 and the pathway it initiates are important for this upregulation. Although we do not currently know why this ECM protein changes occur, we speculate that they constitute an early endogenous proangiogenic attempt from the tissue to re-establish oxygenation of the surrounding tissue.
We thank Drs Feng and van Nostrand for helping us with the MCAO models, and Dr Colognato’s lab for advice. This study was supported by AHA-EIA0540107N and R01NS42168 (SET).
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