Neuroinflammatory Markers in Spontaneously Hypertensive Rat Brain: An Immunohistochemical Study (original) (raw)
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Brain Microglial Cytokines in Neurogenic Hypertension
Hypertension, 2010
Accumulating evidence indicates a key role of inflammation in hypertension and cardiovascular disorders. However, the role of inflammatory processes in neurogenic hypertension remains to be determined. Thus, our objective in the present study was to test the hypothesis that activation of microglial cells and generation of proinflammatory cytokines in the PVN contributes to neurogenic hypertension. Intracerebroventricular infusion of minocycline, an anti-inflammatory antibiotic, caused a significant attenuation of mean arterial pressure, cardiac hypertrophy and plasma norepinephrine induced by chronic Ang II infusion. This was associated with decreases in the numbers of activated microglia and mRNAs for interleukin-1β interleukin-6, and tumor necrosis factor α , and an increase in the mRNA for interleukin-10 in the PVN. Over expression of interleukin-10 induced by recombinant adeno-associated virus-mediated gene transfer in the PVN mimicked the antihypertensive effects of minocycline. Furthermore acute application of a proinflammatory cytokine, interleukin-1β, into the left ventricle or the PVN in normal rats resulted in a significant increase in MAP. Collectively this indicates that angiotensin II-induced hypertension involves activation of microglia, and increases in proinflammatory cytokines in the PVN. These data have significant implications on the development of innovative therapeutic strategies for the control of neurogenic hypertension.
(Peri)vascular production and action of pro-inflammatory cytokines in brain pathology
Clinical Science, 2007
In response to tissue injury or infection, the peripheral tissue macrophage induces an inflammatory response through the release of IL-1β (interleukin-1β) and TNFα (tumour necrosis factor α). These cytokines stimulate macrophages and endothelial cells to express chemokines and adhesion molecules that attract leucocytes into the peripheral site of injury or infection. The aims of the present review are to (i) discuss the relevance of brain (peri)vascular cells and compartments to bacterial meningitis, HIV-1-associated dementia, multiple sclerosis, ischaemic and traumatic brain injury, and Alzheimer's disease, and (ii) to provide an overview of the production and action of pro-inflammatory cytokines by (peri)vascular cells in these pathologies of the CNS (central nervous system). The brain (peri)vascular compartments are highly relevant to pathologies affecting the CNS, as infections are almost exclusively blood-borne. Insults disrupt blood and energy flow to neurons, and active b...
The Journal of Comparative Neurology, 2004
Interleukin-1 (IL-1) is thought to act on the brain to induce fever, neuroendocrine activation, and behavioral changes during disease through induction of prostaglandins at the blood-brain barrier (BBB). However, despite the fact that IL-1 induces the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in brain vascular cells, no study has established the presence of IL-1 receptor type 1 (IL-1R1) protein in these cells. Furthermore, although COX inhibitors attenuate expression of the activation marker c-Fos in the preoptic and paraventricular hypothalamus after administration of IL-1 or bacterial lipopolysaccharide (LPS), they do not alter c-Fos induction in other structures known to express prostaglandin receptors. The present study thus sought to establish whether IL-1R1 protein is present and functional in the rat cerebral vasculature. In addition, the distribution of IL-1R1 protein was compared to IL-1-and LPS-induced COX-2 expression. IL-1R1immunoreactive perivascular cells were mostly found in choroid plexus and meninges. IL-1R1immunoreactive vessels were seen throughout the brain, but concentrated in the preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and ventrolateral medulla. Vascular IL-1R1-ir was associated with an endothelial cell marker, not found in arterioles, and corresponded to the induction patterns of phosphorylated c-Jun and inhibitory-factor kappaB mRNA upon IL-1 stimulation, and colocalized with peripheral IL-1-or LPS-induced COX-2 expression. These observations indicate that functional IL-1R1s are expressed in endothelial cells of brain venules and suggest that vascular IL-1R1 distribution is an important factor determining BBB prostaglandin-dependent activation of brain structures during infection.
Brain inflammation and hypertension: the chicken or the egg?
Journal of neuroinflammation, 2015
Inflammation of forebrain and hindbrain nuclei controlling the sympathetic nervous system (SNS) outflow from the brain to the periphery represents an emerging concept of the pathogenesis of neurogenic hypertension. Angiotensin II (Ang-II) and prorenin were shown to increase production of reactive oxygen species and pro-inflammatory cytokines (interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)) while simultaneously decreasing production of interleukin-10 (IL-10) in the paraventricular nucleus of the hypothalamus and the rostral ventral lateral medulla. Peripheral chronic inflammation and Ang-II activity seem to share a common central mechanism contributing to an increase in sympathetic neurogenic vasomotor tone and entailing neurogenic hypertension. Both hypertension and obesity facilitate the penetration of peripheral immune cells in the brain parenchyma. We suggest that renin-angiotensin-driven hypertension encompasses feedback and feedforward mec...
Journal of Neuroinflammation, 2015
Background: The vasculature of the brain is composed of endothelial cells, pericytes and astrocytic processes. The endothelial cells are the critical interface between the blood and the CNS parenchyma and are a critical component of the blood-brain barrier (BBB). These cells are innately programmed to respond to a myriad of inflammatory cytokines or other danger signals. IL-1β and TNFα are well recognised pro-inflammatory mediators, and here, we provide compelling evidence that they regulate the function and immune response profile of human cerebral microvascular endothelial cells (hCMVECs) differentially.
Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases
Frontiers in Aging Neuroscience
Various age-related diseases involve systemic inflammation, i.e. a stereotyped series of acute immune system responses, and aging itself is commonly associated with low-grade inflammation or inflamm’aging. Neuroinflammation is defined as inflammation-like processes inside the central nervous system, which this review discusses as a possible link between cardiovascular disease-related chronic inflammation and neurodegenerative diseases. To this aim, neuroinflammation mechanisms are first summarized, encompassing the cellular effectors and the molecular mediators. A comparative survey of the best-known physiological contexts of neuroinflammation (neurodegenerative diseases and transient ischemia) reveals some common features such as microglia activation. The recently published transcriptomic characterizations of microglia have pointed a marker core signature among neurodegenerative diseases, but also unraveled the discrepancies with neuroinflammations related with acute diseases of va...
The significance of neuroinflammation in understanding Alzheimer’s disease
Journal of Neural Transmission, 2006
Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0-II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD.
The Role of Inflammation In CNS Injury and Disease
British journal of …, 2006
For many years, the central nervous system (CNS) was considered to be 'immune privileged', neither susceptible to nor contributing to inflammation. It is now appreciated that the CNS does exhibit features of inflammation, and in response to injury, infection or disease, resident CNS cells generate inflammatory mediators, including proinflammatory cytokines, prostaglandins, free radicals and complement, which in turn induce chemokines and adhesion molecules, recruit immune cells, and activate glial cells. Much of the key evidence demonstrating that inflammation and inflammatory mediators contribute to acute, chronic and psychiatric CNS disorders is summarised in this review. However, inflammatory mediators may have dual roles, with detrimental acute effects but beneficial effects in long-term repair and recovery, leading to complications in their application as novel therapies. These may be avoided in acute diseases in which treatment administration might be relatively short-term. Targeting interleukin (IL)-1 is a promising novel therapy for stroke and traumatic brain injury, the naturally occurring antagonist (IL-1ra) being well tolerated by rheumatoid arthritis patients. Chronic disorders represent a greater therapeutic challenge, a problem highlighted in Alzheimer's disease (AD); significant data suggested that anti-inflammatory agents might reduce the probability of developing AD, or slow its progression, but prospective clinical trials of nonsteroidal anti-inflammatory drugs or cyclooxygenase inhibitors have been disappointing. The complex interplay between inflammatory mediators, ageing, genetic background, and environmental factors may ultimately regulate the outcome of acute CNS injury and progression of chronic neurodegeneration, and be critical for development of effective therapies for CNS diseases.
Role of neuroinflammation in hypertension-induced brain amyloid pathology
Alzheimer's & Dementia, 2010
Hypertension and sporadic Alzheimer's disease (AD) have been associated but clear pathophysiological links have not yet been demonstrated. Hypertension and AD share inflammation as a pathophysiological trait. Thus, we explored if modulating neuroinflammation could influence hypertension-induced -amyloid (A) deposition.