Pivotal Roles of Monocytes/Macrophages in Stroke

Stroke is an important issue in public health due to its high rates both of morbidity and mortality, and high rate of disability. Hypertension, cardiovascular disease, arterial fibrillation, diabetes mellitus, smoking, and alcohol abuse are all risk factors for stroke. Clinical observations suggest that inflammation is also a direct risk factor for stroke. Patients with stroke have high levels of inflammatory cytokines in plasma, and immune cells, such as macrophages and T-lymphocytes, are noted within stroke lesions. These inflammatory events are considered as a result of stroke. However, recent studies show that plasma levels of inflammatory cytokines or soluble adhesion molecules are high in patients without stroke, and anti-inflammatory therapy is effective at reducing stroke incidence in not only animal models, but in humans as well. Statins have been shown to decrease the stroke incidence via anti-inflammatory effects that are both dependent and independent of their cholesterol-lowering effects. These reports suggest that inflammation might directly affect the onset of stroke. Microglial cells and blood-derived monocytes/macrophages play important roles in inflammation in both onset and aggravation of stroke lesions. We review the recent findings regarding the role of monocytes/macrophages in stroke.


Introduction
Stroke is the third leading cause of death and a major cause of disability in industrialized countries. Ischemic stroke is the most common type of stroke, occurring in approximately 80% of all strokes [1]. A less common type of stroke is hemorrhagic stroke, which occurs due to a subarachnoid hemorrhage and/or an intracerebral hemorrhage. Hypertension, cardiovascular disease, arterial �brillation, diabetes mellitus, obesity, smoking, and alcohol abuse are risk factors for stroke [2], even if there are slight di�erences in the in�uence of these factors between ischemic stroke and hemorrhagic stroke. However, some stroke patients do not have any of these risk factors, suggesting that other risk factors exist. For many years, clinical observations showed that plasma levels of in�ammatory cytokines were increased aer stroke onset, and immune cells, especially monocytes/macrophages and T-lymphocytes, existed in stroke lesions and related to exaggerate brain damage. In the clinical setting, elevated plasma levels of in�ammatory cytokines, C-reactive protein (CRP), and chemokines are associated with future cardiovascular risk [3]. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and sE-selectin were observed to be increased both in large intracranial artery disease and small-artery disease [4], and plasma levels of ICAM-1 and monocyte chemoattractant protein-1 (MCP-1) were noted to be high in patients with ischemic stroke and myocardial infarction [5,6]. Epidemiological studies have shown that elevated leukocyte count was associated with the risk for �rst-time myocardial infarction and ischemic stroke [7][8][9] and the risk of recurrent myocardial infarction and ischemic stroke in a high-risk population [10]. ese observations indicate that in�ammatory events occur in stroke patients and increase the risk of stroke recurrence. Recently, both clinical and animal studies revealed that these in�ammatory events occurred prior to stroke onset. Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), sICAM-1, sE-selectin, and MCP-1 were elevated in patients with essential hypertension in the absence of other diseases [11][12][13]. Anti-in�ammatory strategies were shown to suppress the incidence of stroke in both human and animal models. ese reports suggest that in�ammation might be a risk factor for stroke. �e review the recent �ndings regarding the role of in�ammation, especially monocytes/macrophages, in ischemic stroke which is predominant type of strokes.

Monocytes/Macrophages and Stroke
2.1. Atherosclerosis. Atherosclerosis is one of the major risk factors for stroke, and monocytes/macrophages affect the brain indirectly by inducing unstable plaques and plaque rupture in atherosclerotic lesions [14]. It is well recognized that atherosclerosis is an in�ammatory disease and macrophages play important roles in the initiation and the progression of atherosclerotic lesion [15]. Accumulation of monocytes/macrophages in the vascular wall occurs early during atherosclerosis [15]. In addition to phagocytosis of oxidized low-density lipoproteins, macrophages secrete interleukin-1 (IL-1 ), tumor necrosis factor-(TNF-), and transforming growth factor-1 (TGF-1). ese in�ammatory cytokines and growth factors induce endothelial dysfunction, smooth muscle cell migration and proliferation, and extracellular matrix production as �brous plaques. During later disease stages, activated macrophages secrete several classes of neutral extracellular proteases, including serine proteases, cathepsins, and matrix metalloproteinases (MMPs) [16]. Blood monocytes already express low levels of a few MMPs [17]; however, contact with matrix leads to rapid upregulation of a broad spectrum of MMPs. Cell biology experiments identify mechanisms by which excessive MMP production can cause plaque rupture, either directly by destruction of extracellular matrix [18] or indirectly through actions that promote death of macrophages [19] and vascular smooth muscle cells [20]. Rupture of unstable plaques may lead to thrombotic stroke onset.

At the Brain.
Monocytes/macrophages directly play important roles in stroke at the brain. Microglial cells, the resident macrophages of the brain, and blood-derived monocytes/macrophages have morphologically and functionally similar roles in stroke [21,22]. Microglial cells are activated rapidly in response to brain injury [23]. is activation occurs within minutes of ischemia onset and induces production of in�ammatory cytokines, including IL-1 and TNF-, which exacerbate tissue damage [24][25][26]. Following the rapid activation of resident microglial cells, blood-derived immune cells in�ltrate into the brain tissue within hours to a few days [21,22]. Most current data from mice models and humans show that blood-derived macrophages are recruited into the ischemic brain tissue, most abundantly at days 3 to 7 aer stroke [27][28][29]. In contrast, resident microglial cells are already activated rapidly on day 1 aer focal cerebral ischemia. Resident microglial cells exist in lesions even at days 4 through 7. ese reports suggest that the resident microglial cell activation is induced immediately aer brain injury and then blood-derived macrophage in�ltration follows. On the other hand, it is reported that macrophages exist in the brain before onset of stroke in stroke-prone spontaneously hypertensive rats (SHRSP) [30,31]. ese �ndings suggest that the alteration of the blood-brain barrier and macrophage activation occurs before the onset of stroke, and these changes might induce stroke onset.

Activation of Immune Cells.
Neutrophils and lymphocytes are also observed in stroke lesions. In ischemic stroke mice model, macrophages started to appear already at 12 hours aer ischemia. On the other hand, lymphocytes (B-and T-lymphocytes) and neutrophils were signi�cantly increased at 3 days aer ischemia [32]. According to this observation, it was reported that macrophages produce in�ammatory cytokines and upregulate adhesion molecules in endothelial cells, thereby promoting neutrophil accumulation and migration into the brain [33]. ese data suggest that macrophage in�ltration occurs prior to other immune cells and macrophage activation attracts other immune cells into stroke lesions. Different subtypes of T-lymphocytes play differential roles in the stroke. CD4 + TH1 cells may progress stroke through releasing proin�ammatory cytokines, including IL-2, IL-12, IFN-, and TNF-, whereas CD4 + TH2 cells may play a protective role through releasing anti-in�ammatory cytokines such as IL-4, IL-5, IL-10, and IL-13 [34]. However, exact role of neutrophils in the stroke is still unclear.

Relationship between Monocytes/ Macrophages and Hypertension
Hypertension is the principal risk factor for stroke and is a leading cause of cognitive decline and dementia [35]. ere is a linear relationship between blood pressure and stroke mortality [36]. Hypertension might induce endothelial cell dysfunction along with macrophage activation and in�ltration into the brain. ere is emerging evidence that monocyte/macrophage in�ltration contributes to hypertension [37].

Endothelial Cell Dysfunction.
Endothelial cell dysfunction is the �rst step of monocytes/macrophages in�ltration into brain. Hypertension might induce endothelial cell dysfunction [38], vascular in�ammation on the vascular lumen [39], and monocyte adhesion [40]. It was reported that hypertension promoted or aggravated endothelial dysfunction, which induced the expression of ICAM-1, P-selectin, and monocyte adhesion in a rat model [40]. High intraluminal pressure activated NF B in an organ culture model of mouse carotid arteries [41]. In humans, the association of chronically or acutely elevated blood pressure with markers of in�ammation has also been documented. Circulating levels of sICAM-1, sVCAM-1, sE-selectin, and MCP-1 are increased in patients with essential hypertension [13,42]. Increasing levels of adhesion molecules and chemoattractant molecules could induce monocyte adhesion on the vascular surface and migration into subendothelial lesions in both aortae and the brain.

Monocyte/Macrophage Activation.
Hypertension might affect blood monocytes directly. e total number of blood Mediators of In�ammation 3 monocytes and activated monocytes is greater in spontaneously hypertensive rats compared with Wistar Kyoto rats, which represent the normotensive control [43,44]. On the other hand, reducing blood pressure with angiotensin converting enzyme inhibitors suppresses endothelial dysfunction and the number of subendothelial macrophages in the aorta [45]. In humans, circulating monocytes from patients with essential hypertension are preactivated compared with those in normotensive healthy individuals. IL-1 secretion of peripheral blood monocytes stimulated by angiotensin II was shown to be signi�cantly higher in patients with essential hypertension compared with normotensive healthy individuals [46].

Renal Dysfunction.
In�ammatory cells accumulate in perivascular regions in the kidney, and in and around glomeruli in hypertensive rats [47,48] and hypertensive subjects [49]. ere is extensive perivascular in�ltration of leukocytes in the kidney of double transgenic rats harboring human renin and angiotensinogen genes. In a study that emphasized the role of in�ammation in blood pressure elevation, pyrrolidine dithiocarbamate, an inhibitor of NF �, prevented monocyte/macrophage in�ltration in animals, reduced expression of ICAM-1 and inducible nitric oxide synthase, and reduced blood pressure [48]. ere is also evidence of macrophage in�ltration in the glomeruli of hypertensive animals [50] and humans [49]. Monocytes/macrophages in the kidney modulate blood pressure via the production of in�ammatory cytokines and modulation of renin-angiotensin-aldosterone system [51,52].
On the other hand, drugs acting on the renin-angiotensinaldosterone system prevent or modulate in�ammation [53]. Monocytes/macrophages might play some important roles in the reciprocal in�uence between in�ammation and hypertension.

Stroke-Prone Spontaneously Hypertensive Rats.
SHRSPs are unique genetic model that mimic both microvessel and parenchymal changes in spontaneous stroke [54,55]. e microvascular changes and brain parenchymal damage may not simply be the result of hypertension, and endothelial cell dysfunction [56] and in�ammation may play a role in brain damage [55]. is animal model has been used to examine the contributions of in�ammation (macrophages) to stroke. In SHRSP, fed a high-salt diet, rosuvastatin treatment signi�cantly delayed the onset of stroke and attenuated the transcription of in�ammatory biomarkers (MCP-1, TGF-1, IL-1 , and TNF-) [57]. Pioglitazone, peroxisome proliferator-activated receptor-agonist, reduced the risk of recurrent stroke in patients with type 2 diabetes [58].
In SHRSP, pioglitazone delayed the onset of stroke by improving vascular endothelial dysfunction, inhibiting brain in�ammation, and reducing oxidative stress [59]. A low dose of acetylsalicylic acid (aspirin) delayed the onset of stroke in SHRSP by suppressing in�ammation [60]. In addition to drug treatments, dietary restriction has been shown to delay the onset of stroke in SHRSP via suppression of systemic and local in�ammation including macrophage in�ltration into the brain [31].

Middle Cerebral Artery
Occlusion. Permanent or transient middle cerebral artery occlusion is an established method for inducing focal ischemic stroke in mice or rats. Middle cerebral artery occlusion produces highly reproducible lesions, and macrophages primarily in�ltrate into the core of the ischemic lesion [61]. e focal ischemic stroke model is a closer approximation to human stroke and produces a heterogeneous pathology that includes a necrotic core and salvageable penumbra [62]. However, small differences in surgical technique may account for different effects on the infarct [63,64]. Furthermore, due to variances in cerebral vascular anatomy, different mouse strains show a different outcome [65,66]. In addition, conditions of animals during surgery, such as blood pressure, blood gases, body temperature, and anesthesia in�uence outcome. us, standardization and quality control are very important when using this animal model.

Hypertensive Mice with Salt
Loading. ere are a lot of hypertensive animal models [67]; however, surgical intervention is needed to induce stroke in these models. Recently, these hypertensive mice have been used to research spontaneous stroke. Excessive salt intake induced frequent thoracic or abdominal cavity hemorrhage in Tsukuba hypertensive mice, which are human renin and angiotensinogen transgenic mice [68]. Hemorrhaging occurred due to the development of aortic aneurysms and rupture at the aortic arch and aorta near the renal arteries. Vascular lesions progressed with structural degeneration of the aortic media. Unfortunately, cerebral pathology was not assessed in this model [68]. Subsequently, a spontaneous stroke model using human renin and angiotensinogen transgenic hypertensive mice, but not Tsukuba hypertensive mice, was reported [69]. In this report, high-salt diet and L-NAME diet induced hemorrhage in the brain stem, cerebellum, and basal ganglia, which were reasonably similar to those observed in patients with hypertension. It is not clari�ed whether these mice models show ischemic stroke; however, these hypertensive mice, especially renin and angiotensinogen transgenic mice, are useful for experimental stroke research.

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In�ammatory cytokines, such as IL-1 , IL-6, and TNF-, are secreted by activated microglial cells and macrophages in stroke lesions and induce the expression of chemokines, which recruit more circulating monocytes/macrophages into lesions and lead to further brain damage. However, the role of each cytokine in stroke is complicated.

Interleukin-1 .
Recently, IL-1 has been considered a therapeutic target for stroke. Chronic increases in IL-1 expression in the brain led to leukocyte in�ltration and increased MCP-1 and ICAM-1 expressions in a mouse model [70], which is a phenotype also seen in stroke lesions. In addition, a number of studies have demonstrated that inhibiting the release or action of IL-1 markedly reduced ischemic cerebral damage in animal models. IL-1 and IL-1 double knockout mice exhibited dramatically reduced ischemic infarct volume compared with wild-type mice [71]. In a meta-analysis of animal model studies, IL-1 receptor antagonist (IL-1Ra), which represents the most advanced approach to modify IL-1 action, reduced infarct volume in models of focal cerebral ischemia [72]. In humans, a phase II clinical trial of intravenous IL-1Ra compared with placebo in patients with acute stroke is currently underway [73]. Further, IL-1Ra gene polymorphism represents a risk factor for ischemic stroke [74,75]. ese reports suggest that inhibition of IL-1 signals can prevent the onset of stroke.

Interleukin-6.
A prospective cohort study and systemic review revealed that plasma levels of IL-6 were associated with poor outcome aer both ischemic and hemorrhagic strokes [76]; however, it was not clear whether IL-6 increased before or aer stroke onset. Animal models showed less association between IL-6 and stroke. IL-6 could not induce adhesion molecules and MCP-1 mRNA expressions in cerebrovascular endothelial cells derived from SHRSP [31]. Mice de�cient in IL-6 showed similar stroke lesion volume and neurological function as control mice in an acute ischemic injury model [77]. Furthermore, IL-6 mediates anti-in�ammatory effects in addition to its proin�ammatory role [78]. erefore, its manipulation can have either detrimental or bene�cial effects. Further studies are required to clarify the role of IL-6 in stroke.

Tumor Necrosis Factor-.
Increased serum and cerebrospinal �uid levels of TNF-have been found in patients 24 hours, 1 week, and 2 weeks aer stroke, and these increases correlate with infarct volume and severity of neurological impairment [79]. However, previous reports suggest that TNF-has a dual role in brain injury [80,81]. Blockade of TNF-actions reduced infarct volume aer permanent middle cerebral artery occlusion in BALB/C mice with the dimeric type I soluble TNF receptor, which binds to TNF-and antagonizes its action [82]. In contrast, TNFpretreatment was neuroprotective against permanent middle cerebral artery occlusion in BALB/C mice with reduction of infarct size, macrophages, and CD11b-positive neutrophils [83]. In addition to these observations, pentoxifylline, an anti-in�ammatory agent, attenuated damage of stroke via the dual role of TNF-. Pentoxifylline treatment increased serum levels of TNF-, but not IL-1 and IL-6, and dose dependently prevented the occurrence of spontaneous brain damage by reducing macrophage in�ltration into lesion in SHRSP [84], suggesting a protective role of TNF-. On the other hand, pentoxifylline reduced brain edema in a rat model of transient focal cerebral ischemia through a decline in TNF-production [85], suggesting an deleterious role of TNF-. Although anti-TNF-strategies have proved bene�cial in other clinical settings such as in�ammatory bowel disease, there are no clinical trials of anti-TNF-agents in stroke. Further studies are required to clarify the role of TNF-in stroke.

MCP-1. CC chemokine ligand (CCL2) is known as
MCP-1 and is a potent mononuclear cell attractant. MCP-1 is synthesized by several cell types, such as monocytes/macrophages, T-lymphocytes, smooth muscle cells, endothelial cells, and even cerebrovascular endothelial cells. �xpression of MCP-1 is upregulated by in�ammatory cytokines. Serum levels of MCP-1 are high in patients with ischemic stroke and myocardial infarction [5,6], which might be interpreted as a stroke-induced increases in in�ammatory events. On the other hand, there is one report that serum CCL2 levels in acute ischemic stroke patients did not differ from that in controls at 1 to 3 days aer stroke onset [86].
In this paper, details of controls were not shown, but one of the possibilities is that control subjects were hypertensive. It is reported that plasma levels of MCP-1 were elevated in patients with essential hypertension in the absence of other diseases [13]. e MCP-1-de�cient mice model is a unique model to elucidate the role of macrophages in stroke [87]. Compared with control mice, infarct volume was smaller in MCP-1-de�cient mice 24 hours aer middle cerebral artery occlusion, and a reduction of phagocytic macrophage accumulation within infarcts and the infarct border in MCP-1 de�cient mice 2 weeks aer middle cerebral artery occlusion. In addition, MCP-1 de�cient mice produced less IL-1 in ischemic tissue. is means that MCP-1 and IL-1 are key factors of macrophages in stroke lesions.

Adipokines.
Obesity is also recognized as the risk factor for stroke, because obesity is associated with hypertension and in�ammation via secretion of adipokines, such as adiponectin, leptin, resistin, adipsin, plasminogen activator inhibitor-1, and in�ammatory cytokines [88][89][90]. It is well known that macrophage in�ltration into adipose tissue induces in�ammation in adipose tissue and in�uences these adipokine secretions [91,92]. e most commonly studied adipocytokines are leptin and adiponectin. ere are a lot of reports about the association of leptin and adiponectin with stroke, and leptin and adiponectin show differential association patterns with ischemic stroke [93]. It is reported that higher leptin levels and lower adiponectin levels were found in stroke patients [94]. On the other hand, there are controversial reports that adiponectin, but not leptin, levels are recognized as a predictor of the risk for stroke [95], or that leptin, but not adiponectin, levels are recognized as a predictor of the risk for stroke in men, but not women [96]. It is not clear whether adiponectin and leptin are useful predictors of stroke in obese subjects; however, adiponectin and leptin might directly in�uence stroke incidence. It is reported that leptin stimulates macrophages and that adiponectin suppresses it. Leptin increases the mRNA and protein levels of IL-1 , IL-6, IL-12, TNF-, cyclooxygenase-2, and MCP-1 in macrophages and endothelial cells [97,98]. Adiponectin inhibits pro-in�ammatory signaling in human macrophages [99] and promotes macrophage polarization toward an anti-in�ammatory phenotype [100]. Adiponectin also increases Hypertension ↑ Inflammation ↑ IL-1 IL-6 TNF-F 1: Monocytes/macrophages modulate adipose tissue and kidney functions and accelerate stroke. Monocytes/macrophages in�ltration into adipose tissue stimulates secretion of leptin and in�ammatory cytokines and suppresses secretion of adiponectin, which induce systemic in�ammation, endothelial cell dysfunction, and monocytes/macrophages activation. Monocytes/macrophages in�ltration into kidney modulates renin-angiotensin system and increase blood pressure, which also induces endothelial cell dysfunction and monocytes/macrophages activation. Endothelial cells express MCP-1 and adhesion molecules, which induce monocytes chemotaxis, adhesion, and migration into subendothelial lesions. Microglial cells and in�ltrated monocytes/macrophages in brain induce cerebrovascular damages and cause stroke onset. IL-10, an anti-in�ammatory cytokine, as well as mR�A expression in human monocyte-derived macrophages [101]. In addition, both adiponectin and leptin receptors are expressed in the brain, suggesting that these adipokines might be directly associated with stroke [102,103].
ere are several reports that treatment with drugs that have anti-in�ammatory properties can prevent stroke not only in animal models, but also in humans.

Statins.
Rosuvastatin treatment signi�cantly delayed the onset of stroke and attenuated the transcription of in�ammatory biomarkers [57]. Clinical studies using statins already use in�ammatory events as endpoints for stroke prevention. In healthy persons without hyperlipidemia but with elevated high-sensitivity CRP levels, rosuvastatin, which lowered high-sensitivity CRP as well as cholesterol levels, reduced the incidence of stroke and myocardial infarction by 50% relative to placebo [104]. A meta-analysis of statin trials showed that statins might reduce the incidence of all strokes by decreasing LDL-cholesterol without increasing the incidence of hemorrhagic stroke [105]. In addition to cholesteroldependent effects, cholesterol-independent effects of statins on stroke have also been recognized [106,107]. However, statin treatment increases the risk of hemorrhagic stroke in patients with a history of cerebrovascular disease, even though it also clearly decreased the risk of ischemic stroke [108]. erefore, patients undergoing statin treatment should be carefully monitored to avoid achieving very low level of cholesterols, which are known risk for hemorrhagic stroke [109].
6.2. iazolizinediones. iazolidinediones, including rosiglitazone and pioglitazone, are peroxisome proliferatoractivated receptor-(PPAR-) agonists used in the treatment of type 2 diabetes. A systemic review showed that rosiglitazone and pioglitazone were similarly effective in reducing infarct volume and protecting neurologic function in a rodent model of focal or global cerebral ischemia [110]. Pioglitazone delayed the onset of stroke by improving vascular endothelial dysfunction and brain in�ammation in SHRSP. Pioglitazone suppressed macrophage in�ltration, MCP-1 and TNF-gene expressions in the brain [59]. Rosiglitazone induced upregulation of CD36 in macrophages and enhanced the ability of microglia to phagocytose red blood cells, which helped to improve hematoma resolution, and improved functional de�cits in an intracerebral hemorrhage mouse model [111]. In humans, the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) [112] showed that pioglitazone signi�cantly reduced the risk of recurrent stroke in high-risk patients with type 2 diabetes [58]. On the other hand, one report showed that compared with pioglitazone, rosiglitazone was associated with an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of acute myocardial infarction, stroke, heart failure, or all-cause mortality in patients of 65 years or older [113].
���� �ther Anti�In�a��ator� Dru�s� Low-dose acetylsalicylic acid (aspirin) also delayed the onset of stroke in SHRSP via suppression of in�ammation [60]. Aspirin reduced saltinduced macrophage accumulation and MMP-9 activity at the stroke-negative area in the cerebral cortex of SHRSP [60]. Frequent aspirin use might also confer a protective effect for risk of stroke in humans [114,115]. Terutroban, a speci�c thromboxane/prostaglandin endoperoxide receptor antagonist, decreased cerebral mRNA expressions of IL-1 , transforming growth factor-, and MCP-1 and increased survival in SHRSP [116]. ese effects were similar to rosuvastatin and aspirin [116]. e Prevention of cerebrovascular and cardiovascular Events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study was started in February 2006 [117]. Recently, it was reported that PERFORM study did not meet the prede�ned criteria for noninferiority, but showed similar rates to terutroban and aspirin for the primary endpoint, such as a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal myocardial infarction, or other vascular death [118]. ese reports indicate that antiplatelets agents, which also have anti-in�ammatory properties, could suppress in�ammation and prevent stroke onset.

�. �ene�c�a� R��es af�er S�r��e
It is generally believed that the activated microglial cells in ischemic injury are neurotoxic, and results of several recent studies revealed that microglial cells might exert neuroprotective effects in certain conditions [119,120]. In addition to the primary role of macrophages, which is the phagocytosis of cellular and �brillar debris resulting from stroke, activated microglial cells and macrophages are involved in regulation of the regenerative state and remodeling of the brain by producing brain-derived neurotrophic factor [121,122], insulin growth factor 1 [123,124], several other growth factors [125], neuroprotective gene Ym1 [126], and nitric oxide which are known to regulate synaptic functions [127]. As described previously, some cytokines secreted from microglial cells and macrophages, such as IL-6 and TNF-, and attenuate brain damage. In addition to these mediators, intracranial transplantation of monocyte-derived multipotential cells enhances recovery aer ischemic stroke [128]. Whether activated microglial cells and macrophages act as toxic or neuroprotective factors might depend on the time and severity of stroke lesions.

Summary
Microglial cells and monocytes/macrophages play important roles in the onset and aggravation of stroke via expression of several in�ammatory cytokines at the brain, adipose tissue, and kidney ( Figure 1). However, it is also reported that these in�ammatory events are important in the reduction of and recovery from brain damage. However, it is clear that suppression of in�ammation is effective in the prevention of primary stroke, and macrophages might be therapeutic targets to prevent stroke. ��n��c� �f �n�eres�s e authors have no con�ict of interests to disclosure.