Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood–brain barrier. However, immune responses do occur in the brain in ...neurological conditions in which the integrity of the blood–brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions.
Stroke leads to long term sensory, motor and cognitive impairments. Most patients experience some degree of spontaneous recovery which is mostly incomplete and varying greatly among individuals. The ...variation in recovery outcomes has been attributed to numerous factors including lesion size, corticospinal tract integrity, age, gender and race. It is well accepted that genetics play a crucial role in stroke incidence and accumulating evidence suggests that it is also a significant determinant in recovery. Among the number of genes and variations implicated in stroke recovery the val66met single nucleotide polymorphism (SNP) in the BDNF gene influences post-stroke plasticity in the most significant ways. Val66met is the most well characterized BDNF SNP and is common (40–50 % in Asian and 25–32% in Caucasian populations) in humans. It reduces activity-dependent BDNF release, dampens cortical plasticity and is implicated in numerous diseases. Earlier studies on the effects of val66met on stroke outcome and recovery presented primarily a maladaptive role. Novel findings however indicate a much more intricate interaction between val66met and stroke recovery which appears to be influenced by lesion location, post-stroke stage and age. This review will focus on the role of BDNF and val66met SNP in relation to stroke recovery and try to identify potential pathophysiologic mechanisms involved. The effects of age on val66met associated alterations in plasticity and potential consequences in terms of stroke are also discussed.
Stroke pathology involves multifactorial pro-death responses, including inflammation, oxidative stress, vascular dysfunction, and activation of necrotic and apoptotic pathways. The interruption of a ...single specific pathway in defined stroke model systems has not been sufficient to address the multifactorial nature of stroke-induced injuries in the human population. CD36 is a class B scavenger receptor that functions in regulating normal physiological and pathological functions. CD36 pathways are activated by several distinct ligands. Convergence of these pathways results in inflammatory responses and endothelial dysfunction, which may be an underlying cause of cardio- and cerebrovascular diseases. The current review describes receptor CD36-ligand interactions relevant to endothelial function and discusses how targeting CD36 may have therapeutic utility in stroke.
Novel therapeutic intervention that aims to enhance the endogenous recovery potential of the brain during the subacute phase of stroke has produced promising results. The paradigm shift in treatment ...approaches presents new challenges to preclinical and clinical researchers alike, especially in the functional endpoints domain. Shortcomings of the “neuroprotection” era of stroke research are yet to be fully addressed. Proportional recovery observed in clinics, and potentially in animal models, requires a thorough reevaluation of the methods used to assess recovery. To this end, this review aims to give a detailed evaluation of functional outcome measures used in clinics and preclinical studies. Impairments observed in clinics and animal models will be discussed from a functional testing perspective. Approaches needed to bridge the gap between clinical and preclinical research, along with potential means to measure the moving target recovery, will be discussed. Concepts such as true recovery of function and compensation and methods that are suitable for distinguishing the two are examined. Often-neglected outcomes of stroke, such as emotional disturbances, are discussed to draw attention to the need for further research in this area.
Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; ...however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor (BDNF) gene that results in the substitution of a valine with a methionine at codon 66 (Val66Met) occurs with a high frequency in humans. This study addressed the effect of genetic variability in developing obesity and the efficacy of the inhibition of cluster of differentiation 36 (CD36), a multifunctional receptor implicated in obesity and insulin resistance, in WT mice and mice with the BDNF Val66Met variant. CD36 inhibition by salvionolic acid B (SAB) in diet-induced obese WT mice reduced visceral fat accumulation and improved insulin resistance. The benefit of SAB was abrogated in CD36 knockout mice, showing the specificity of SAB. In addition, mice with the Val66Met variant in both alleles (BDNFM/M) fed a high-fat diet exhibited extreme obesity with increased CD36 gene and protein levels in macrophages. Chronic SAB treatment in BDNFM/M mice significantly decreased visceral fat accumulation and improved insulin resistance. Notably, the effect of SAB was greater in the extremely obese BDNFM/M mice compared with the WT mice. The study demonstrated a link between BDNF Val66Met and elevated CD36 expression and suggested that CD36 inhibition may be a potential strategy to improve metabolic dysfunctions and to normalize risk factors for vascular diseases in the obese population.
Infiltrating monocyte-derived macrophages (M-MΦ) influence stroke-induced brain injury. Although the inflammatory nature of M-MΦ in acute stroke has been well documented, their role during the ...resolution phase of stroke is less clear. With emerging evidence for the involvement of scavenger receptors in innate immunity, this study addresses an M-MΦ CD36 role in mediating phagocytosis during the recovery phase of stroke. Stroke increases CD36 and TSP-1/2 mRNA levels in the ipsilateral hemisphere at acute (3-day (d)) and recovery (7d) periods. Quantification of total, intracellular, and cell surface CD36 protein levels showed relatively unchanged expression at 3d post-ischemia. At 7d, there was a significant increase in cell surface CD36 (p < 0.05) with a concurrent reduction of intracellular CD36 (p < 0.05) in the ipsilateral hemisphere. Both cell surface and intracellular CD36 were found in whole brain lysates, whereas cell surface CD36 was predominantly detected in isolated brain mononuclear cells, blood monocytes, and peritoneal macrophages, suggesting that cell surface CD36 expressed in the post-ischemic brain originates from the periphery. The stroke-induced CD36 mRNA level correlated with increased expression of lysosomal acid lipase, an M2 macrophage marker. Functionally, higher CD36 expression in M-MΦ is correlated with higher phagocytic indices in post-ischemic brain immune cells. Moreover, pharmacological inhibition of CD36 attenuated phagocytosis in peritoneal macrophages and brain M-MΦ. These findings demonstrate that cell surface CD36 on M-MΦ mediates phagocytosis during the recovery phase in post-stroke brains and suggests that CD36 plays a reparative role during the resolution of inflammation in ischemic stroke.
Monocytes/macrophages (MMs), mononuclear phagocytes, have been implicated in stroke-induced inflammation and injury. However, the presence of pro-inflammatory Ly-6Chigh and antiinflammatory Ly-6Clow ...monocyte subsets raises uncertainty regarding their role in stroke pathologic assessment. With recent identification of the spleen as an immediate reservoir of MMs, this current study addresses whether the spleen-derived MMs are required for stroke pathologic assessment. We observed that the spleen was contracted in poststroke animals and the contraction was accompanied by decreased number of Ly-6Chigh and Ly-6Clow subsets in the spleen. The deployment of these subsets from the spleen temporally coincided with respective increases in the ischemic brain. Compared to mice with the spleen, mice receiving a splenectomy just before the stroke displayed less accumulation of Ly-6Chigh and Ly-6Clow MMs in the brain. Despite the reduced accumulation of both subsets, infarct size and swelling were not reduced in the asplenic mice. The dissociative findings of infarct size and extent of MM infiltration in the postischemic brain indicate minimal involvement of spleen-derived total MMs in acute infarct development. Selective Ly-6Chigh or Ly-6Clow MM targeting is suggested to address the contribution of the individual subset to acute stroke pathologic assessment.
BACKGROUND AND PURPOSE—Stroke-induced acute severe body weight (BW) loss is associated with a high rate of mortality during a critical poststroke period. Several interventions to reduce weight loss, ...however, have not been successful. Currently, the biological significance of this extraordinary catabolic process is not well understood. Spleen-derived monocytes/macrophages (MMs) are the major immune cells recruited to the injured brain. The trafficking of MMs has been shown to be important for tissue repair and recovery. The purpose of the study is to investigate whether the BW reduction is essential for MM-mediated immune response for mice to survive and whether a corticosterone-mediated catabolic event underlies the processes.
METHODS—C57BL/6 male mice (12-week-old) were subjected to transient middle cerebral artery occlusion. BW, total MMs, and their Ly-6C and Ly-6C subsets were determined in the spleen, blood, and the brain in poststroke mice. Poststroke survival rate and MM subsets were determined in mice with adrenalectomy, sham-adrenalectomy, and adrenalectomy mice supplemented with corticosterone.
RESULTS—Stroke reduced BW with a maximum reduction at day 3 poststroke (17.2±5.2%). The reduction at day 3 was positively linked to injury severity and selective depletion of MMs, but no other types of immune cells, in the spleen. Notably, the splenic MM depletion was significantly greater in mice with severe BW reduction (≥18% at day 3). In the blood, stroke depleted circulating MMs to a similar degree in animals with moderate and severe BW loss. Ly-6C+ monocyte infiltration in the poststroke brain was greater in mice with severe BW loss. Blocking the catabolic process by adrenalectomy significantly increased poststroke mortality, but the mortality was partially rescued by corticosterone supplement in adrenalectomy mice.
CONCLUSIONS—Stroke-induced BW loss facilitates MM-mediated immune response, and the adrenal corticosterone-mediated catabolic process is necessary for poststroke survival.
Monocyte-derived macrophages (MDMs) and microglia elicit neural inflammation and clear debris for subsequent tissue repair and remodeling. The role of infiltrating MDMs in the injured brain, however, ...has been controversial due to overlapping antigen expression with microglia. In this study, we define the origin and function of MDMs in cerebral ischemia.
Using adoptive transfer of GFP
splenocytes into adult asplenic mice subjected to transient middle cerebral artery occlusion, we compared the role of CD11b
/CD45
/NK1.1
/Ly6G
MDMs and microglia in the ischemic brain. The phagocytic activities of MDMs and microglia were measured by the uptake of fluorescent beads both in vivo with mice infused with GFP
splenocytes and ex vivo with cultures of isolated brain immune cells.
Stroke induced an infiltration of MDMs GFP+ into the ipsilateral hemisphere at acute (3 days) and sub-acute phases (7 days) of post-stroke. At 7 days, the infiltrating MDMs contained both CD45
and CD45
subsets. The CD45
MDMs in the injured hemisphere exhibited a significantly higher proliferation capacity (Ki-67 expression levels) as well as higher expression levels of CD11c when compared to CD45
MDMs. The CD45
and CD45
MDM subsets in the injured hemisphere were approximately equal populations, indicating that CD45
MDMs infiltrating the ischemic brain changes their phenotype to CD45
microglia-like phenotype. Studies with fluorescent beads reveal high levels of MDM phagocytic activity in the post-stroke brain, but this phagocytic activity was exclusive to post-ischemic brain tissue and was not detected in circulating monocytes. By contrast, CD45
microglia-like cells had low levels of phagocytic activity when compared to CD45
cells. Both in vivo and ex vivo studies also show that the phagocytic activity in CD45
MDMs is associated with an increase in the CD45
/CD45
ratio, indicating that phagocytosis promotes MDM phenotype conversion.
This study demonstrates that MDMs are the predominant phagocytes in the post-ischemic brain, with the CD45
subset having the highest phagocytic activity levels. Upon phagocytosis, CD45
MDMs in the post-ischemic brain adopt a CD45
phenotype that is microglia-like. Together, these studies reveal key roles for MDMs and their phagocytic function in tissue repair and remodeling following cerebral ischemia.
The astrocytic response to injury is characterized on the cellular level, but our understanding of the molecular mechanisms controlling the cellular processes is incomplete. The astrocytic response ...to injury is similar to wound-healing responses in non-neural tissues that involve epithelial-to-mesenchymal transitions (EMTs) and upregulation in ZEB transcription factors. Here we show that injury-induced astrogliosis increases EMT-related genes expression, including Zeb2, and long non-coding RNAs, including Zeb2os, which facilitates ZEB2 protein translation. In mouse models of either contusive spinal cord injury or transient ischemic stroke, the conditional knockout of Zeb2 in astrocytes attenuates astrogliosis, generates larger lesions, and delays the recovery of motor function. These findings reveal ZEB2 as an important regulator of the astrocytic response to injury and suggest that astrogliosis is an EMT-like process, which provides a conceptual connection for the molecular and cellular similarities between astrogliosis and wound-healing responses in non-neural tissue.
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•Zeb2 promotes astrogliosis and preservation of neurological function after injury•Naive astrocytes have Zeb2 mRNA, but protein expression is induced only after injury•Stroke and SCI also modify expression of several lncRNAs, including Zeb2os•Zeb2’s role and gene expression changes suggest astrogliosis is an EMT-like process
Vivinetto et al. identify the EMT-related transcription factor ZEB2 as a regulator of the astrocytic response to injury. Mouse models of either stroke or SCI show that knockout of Zeb2 in astrocytes attenuates astrogliosis, increases lesion sizes, and delays recovery motor function. Altogether, the findings suggest that astrogliosis is an EMT-like process.
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