Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation

D’Mello, Charlotte; Le, Tai; Swain, Mark G.

doi:10.1523/jneurosci.3567-08.2009

Cited by 563 publications

(538 citation statements)

References 76 publications

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“…This process is controlled by cytokine and chemokine signaling and has been shown to affect brain microglia under conditions of inflammation remote to the CNS such as hepatic inflammation (Riazi et al ., 2008; D'Mello et al ., 2009). G3 mTerc −/− mice after 8 months of age start showing prominent signs of intestinal dystrophy and in extreme cases resulting in anal prolapse.…”

Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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SummaryMicroglia are a proliferative population of resident brain macrophages that under physiological conditions self‐renew independent of hematopoiesis. Microglia are innate immune cells actively surveying the brain and are the earliest responders to injury. During aging, microglia elicit an enhanced innate immune response also referred to as ‘priming’. To date, it remains unknown whether telomere shortening affects the proliferative capacity and induces priming of microglia. We addressed this issue using early (first‐generation G1 mTerc−/−)‐ and late‐generation (third‐generation G3 and G4 mTerc−/−) telomerase‐deficient mice, which carry a homozygous deletion for the telomerase RNA component gene (mTerc). Late‐generation mTerc−/− microglia show telomere shortening and decreased proliferation efficiency. Under physiological conditions, gene expression and functionality of G3 mTerc−/− microglia are comparable with microglia derived from G1 mTerc−/− mice despite changes in morphology. However, after intraperitoneal injection of bacterial lipopolysaccharide (LPS), G3 mTerc−/− microglia mice show an enhanced pro‐inflammatory response. Nevertheless, this enhanced inflammatory response was not accompanied by an increased expression of genes known to be associated with age‐associated microglia priming. The increased inflammatory response in microglia correlates closely with increased peripheral inflammation, a loss of blood–brain barrier integrity, and infiltration of immune cells in the brain parenchyma in this mouse model of telomere shortening.

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Section: Discussionmentioning

confidence: 99%

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

et al. 2015

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“…This suggests an influence of the immune system on the brain during increased disease activity (3). Studies in patients with multiple sclerosis and in animal models of autoimmune inflammation of the CNS have shown that increased choline signals, as a marker of cell membrane turnover, are associated with inflammation in the form of monocyte infiltration, rather than demyelination (9,19).…”

Section: Discussionmentioning

confidence: 99%

“…The median number of disease-modifying antirheumatic drugs (DMARDs) taken at the time of the study and previously taken was 3 (range [1][2][3][4][5][6]. DMARD treatment at the time of the study was as follows: infliximab in 1 patient, methotrexate in 22, sulfasalazine in 8, leflunomide in 4, aurothiomalate in 1, azathioprine in 1, and antimalarial drugs in 4.…”

Section: Methodsmentioning

confidence: 99%

Brain involvement in rheumatoid arthritis: A magnetic resonance spectroscopy study

Emmer¹,

Bijl²,

Huizinga³

et al. 2009

Arthritis & Rheumatism

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Objective. Tumor necrosis factor ␣ was recently implicated as an important mediator of communication between the peripheral and cerebral immune systems in an animal model of chronic inflammation. The purpose of this study was to examine by proton magnetic resonance spectroscopy ( 1 H-MRS) the influence of inflammation on cerebral metabolism in patients with rheumatoid arthritis (RA).Methods. Single-voxel 1 H-MRS of the centrum semiovale was performed on 35 RA patients (6 men and 29 women; mean ؎ SD age 51.8 ؎ 14.6 years) and 28 healthy age-and sex-matched control subjects (9 men and 19 women; mean ؎ SD age 50.2 ؎ 10.4 years). None of the study subjects had any neurologic signs or symptoms. Clinical markers of disease activity were correlated with the 1 H-MRS findings.Results. Patients with active RA, as reflected by an elevated erythrocyte sedimentation rate (ESR), had a significantly higher ratio of choline to creatine and a significantly lower ratio of N-acetylaspartate to choline than did patients with inactive RA, as reflected by a normal ESR. Moreover, the ratios of choline to creatine and NAA to choline were significantly correlated with the ESR after correction for age, sex, smoking status, handedness, alcohol consumption, medication use, and disease duration. Medication use had no additional effect on these associations. Conclusion.Our data show that systemic inflammation in RA is associated with metabolic changes in the brain.

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“…The activated microglia produce MCP-1/ CCL2 prior to cerebral monocyte infiltration in response to peripheral TNF-a signaling and in TNF-R1 deficient mice microglial expression of MCP-1/CCL2 and cerebral monocyte recruitment were both markedly inhibited. 74 A whole human genome micro-array approach in post mortem brain samples from cirrhotic patients with or without HE and non-cirrhotic controls, has indicated altered expression levels in over one thousand genes related to oxidative stress, microglial activation, receptor signaling, inflammatory pathways, cell proliferation and apoptosis. Despite an up-regulation of genes associated with microglia activation, proinflammatory cytokine mRNA profiles remained unchanged in the brain of patients with liver cirrhosis and HE as compared to controls supporting the previous findings of the Zemtsova study.…”

Section: The Role Of Systemic Inflammation In Encephalopathy In Chronmentioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

224

185

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The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

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Cerebral Microglia Recruit Monocytes into the Brain in Response to Tumor Necrosis Factorα Signaling during Peripheral Organ Inflammation

Cited by 563 publications

References 76 publications

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

Brain involvement in rheumatoid arthritis: A magnetic resonance spectroscopy study

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

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