Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene-expression profile and phenotype of a variety of endogenous CNS cell types (astrocytes, neurons and microglia), as well as an influx of leukocytic cells (neutrophils, macrophages and T-cells) from the periphery. Many molecules and conditions can trigger a transformation of surveying microglia to microglia of an alerted or reactive state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. In particular, we focus on the role of specific molecular signaling systems, such as hypoxia inducible factor-1 and Toll-like receptor-4, in regulating the microglial response in this setting. We then review histological and novel radiological data that confirm a key role for microglial activation in the setting of ischemic stroke in humans. We also discuss recent progress in the pharmacologic and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in pre-emptively targeting microglial activation in order to reduce stroke severity.
Cell culture studies demonstrating that the serine protease thrombin can induce neuronal and glial process retraction, glial proliferation, and changes in gene expression suggest a role for thrombin in CNS development, plasticity, and response to injury. Most cellular responses to thrombin are mediated by proteolytic activation of the cloned thrombin receptor (TR), a member of the seven transmembrane domain, G-protein-coupled receptor superfamily. As a step toward understanding the role of thrombin and its receptor in the CNS, Northern blot, in situ hybridization, and immunohistochemical techniques were used to analyze the cellular localization of TR mRNA in weanling-age rat brain. TR mRNA was broadly distributed across the neuraxis, although expression was very focal and often anatomically limited within specific neural structures. The greatest hybridization was associated with individual neurons in neocortex, cingulate/retrosplenial cortex, and subiculum, subsets of nuclei in hypothalamus, thalamus, pretectum, and ventral mesencephalon, and discrete cell layers in the hippocampus, cerebellum, and olfactory bulb. Patterns of hybridization included neuronal, glial, and ependymal cells, although white matter was uniformly negative, as were most cerebrovascular endothelial cells. Expression of TR mRNA by astroglia and dopaminergic neurons was confirmed by colocalization with immunoreactivity for glial fibrillary acidic protein (GFAP) in hippocampus and tyrosine hydroxylase in the substantia nigra. Comparison between TR and prothrombin (thrombin's precursor) cRNA hybridization demonstrated distinct but overlapping brain distributions of these transcripts, most clearly evident in postnatally developing, laminated structures. These results suggest widespread utilization of, and multiple physiologic, and possibly pathophysiologic, functions for, the thrombin/TR cell signaling system in the CNS.
SUMMARY: RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental vasoconstriction in multiple cerebral arteries. The angiographic appearance resembles vasculitis, except that the abnormalities resolve during the course of several months. Because the treatment of RCVS differs from that for vasculitis, radiologists must understand the clinical and radiologic features so as to better guide imaging algorithms and facilitate diagnosis. We present a series of 6 cases of RCVS that highlight the imaging features across multiple modalities.ABBREVIATIONS: IPH ϭ intraparenchymal hemorrhage; MIP ϭ maximum intensity projection; NSAID ϭ nonsteroidal anti-inflammatory drug; PACNS ϭ primary angiitis of the CNS; PRES ϭ posterior reversible encephalopathy syndrome; RCVS ϭ reversible cerebral vasoconstriction syndrome; SDH ϭ subdural hematoma; TCD ϭ transcranial Doppler R CVS is an under-recognized clinical-radiologic entity characterized by a history of sudden severe headaches, sometimes associated with ischemic or hemorrhagic stroke, focal neurologic deficits, or seizures. First described by Call et al in 19881 , RCVS encompasses a wide variety of entities previously described by other names, including postpartum angiopathy, migrainous vasospasm, migrainous stroke, druginduced angiopathy, and benign angiopathy of the CNS. 2,3The condition is defined by reversible segmental cerebral vasoconstriction on angiography.1-3 The angiographic findings are similar to those of other vasculopathies, including PACNS.4 Unlike PACNS, the vascular abnormalities of RCVS resolve within several months. 1,2,5,6 RCVS typically occurs following exposure to a trigger, commonly sympathomimetic or vasoactive agents, including amphetamines, phenylpropanolamine, pseudoephedrine, serotonergic antidepressants, nicotine, caffeine, cannabis, and triptan-or ergot-containing medications.2,7-9 Other triggers include the peripartum period, 10 eclampsia, strenuous physical activity, bathing or showering, sexual activity, and binge alcohol drinking.2 Most patients with RCVS are young and middle-aged women. 3Patients with RCVS exhibit a range of parenchymal abnormalities, including convexal SAH, IPH, ischemic infarcts, and PRES.2,9,11-13 Alternatively, imaging findings may be normal.2,9 Findings of CSF analysis are usually normal or nearnormal.3 Because of the overlap with other causes of headache and stroke in adults and because the vascular abnormalities early in the course of the disease may be subtle or absent, the diagnosis of RCVS is easily missed. Early recognition of RCVS allows appropriate clinical management aimed at reducing the frequency, duration, and severity of vascular complications, primarily through identification and removal of triggers. Because management and outcome of RCVS differ from those of other vasculopathies, it is critical that radiologists recognize its typical imaging appearance, time course, and clinical features. Case Series...
Microglia, innate immune cells of the CNS, sense infection and damage through overlapping receptor sets. Toll-like receptor (TLR) 4 recognizes bacterial lipopolysaccharide (LPS) and multiple injury-associated factors. We show that its co-receptor CD14 serves three non-redundant functions in microglia. First, it confers an up to 100-fold higher LPS sensitivity compared to peripheral macrophages to enable efficient proinflammatory cytokine induction. Second, CD14 prevents excessive responses to massive LPS challenges via an interferon β-mediated feedback. Third, CD14 is mandatory for microglial reactions to tissue damage-associated signals. In mice, these functions are essential for balanced CNS responses to bacterial infection, traumatic and ischemic injuries, since CD14 deficiency causes either hypo- or hyperinflammation, insufficient or exaggerated immune cell recruitment or worsened stroke outcomes. While CD14 orchestrates functions of TLR4 and related immune receptors, it is itself regulated by TLR and non-TLR systems to thereby fine-tune microglial damage-sensing capacity upon infectious and non-infectious CNS challenges.
Neuroinflammation occurs in acute and chronic CNS injury, including stroke, traumatic brain injury and neurodegenerative diseases. Microglia are specialized resident myeloid cells that mediate CNS innate immune responses. Disease relevant stimuli such as reactive oxygen species (ROS) can influence microglia activation. Previously we observed that p53, a ROS responsive transcription factor, modulates microglia behaviors in vitro and in vivo, promoting pro-inflammatory functions and suppressing down-regulation of the inflammatory response and tissue repair. Here we describe a novel mechanism by which p53 modulates the functional differentiation of microglia both in vitro and in vivo. Adult microglia from p53deficient mice have increased expression of the anti-inflammatory transcription factor c-Maf. To determine how p53 negatively regulates c-Maf, we examined the impact of p53 on known c-Maf regulators. MiR-155 is a microRNA (miRNA) that targets c-Maf. We observed that cytokine induced expression of miR-155 was suppressed in p53 deficient microglia. Furthermore, Twist2, a transcriptional activator of c-Maf, is increased in p53 deficient microglia. We identified recognition sites in the 3′ untranslated region of Twist2 mRNA that are predicted to interact with two p53 dependent miRNAs: miR-34a and miR-145. Here we demonstrate that miR-34a and -145 are regulated by p53 and negatively regulate Twist2 and c-Maf expression in microglia and the RAW macrophage cell line. Taken together, these findings support the hypothesis that p53 activation induced by local ROS or accumulated DNA damage, influences microglia functions and that one specific molecular target of p53 in microglia is c-Maf.
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