Microglial activation and TNFα production mediate altered CNS excitability following peripheral inflammation

Riazi, Kiarash; Galic, Michael A.; Kuzmiski, J. Brent; Ho, Winnie; Sharkey, Keith A.; Pittman, Quentin J.

doi:10.1073/pnas.0806682105

Cited by 366 publications

(336 citation statements)

References 64 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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“…Wogonin has antioxidant properties and can induce apoptosis of cells that have been previously sensitized by TNF-␣ (36,37). Minocycline has anti-inflammatory properties that lead to lower CNS excitability (38). Flow cytometry was performed on cells isolated on day 3 p.i.…”

Section: Cd11bmentioning

confidence: 99%

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Cusick

Libbey

Patel

et al. 2013

J Virol

101

173

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b Viral infections of the central nervous system (CNS) can trigger an antiviral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. The extent of the proinflammatory response in the CNS and the timing of the release of proinflammatory cytokines can lead to neuronal excitability. Tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6), two proinflammatory cytokines, have been linked to the development of acute seizures in Theiler's murine encephalomyelitis virus-induced encephalitis. It is unclear the extent to which the infiltrating macrophages versus resident CNS cells, such as microglia, contribute to acute seizures, as both cell types produce TNF-␣ and IL-6. In this study, we show that following infection a significantly higher number of microglia produced TNF-␣ than did infiltrating macrophages. In contrast, infiltrating macrophages produced significantly more IL-6. Mice treated with minocycline or wogonin, both of which limit infiltration of immune cells into the CNS and their activation, had significantly fewer macrophages infiltrating the brain, and significantly fewer mice had seizures. Therefore, our studies implicate infiltrating macrophages as an important source of IL-6 that contributes to the development of acute seizures.

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“…Seizure susceptibility was also assessed using an intravenous (IV) infusion of pentylenetetrazol (PTZ) into the jugular vein of adult rats as previously described Riazi et al, 2008). Briefly, jugular vein catheters were surgically implanted under ketamine/xylazine (85:15) anaesthesia, into adult rats which previously received ICV SAL (n=10) or POLY I:C (n=6) at P14.…”

Section: Pentylenetetrazol Seizure Susceptibility Testingmentioning

confidence: 99%

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

Galic

Riazi

Henderson

et al. 2009

Neurobiology of Disease

101

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Viral infections of the CNS and their accompanying inflammation can cause long-term neurological effects, including increased risk for seizures. To examine the effects of CNS inflammation, we infused polyinosinic: polycytidylic acid, intracerebroventricularly to mimic a viral CNS infection in 14 day-old rats. This caused fever and an increase in the pro-inflammatory cytokine, interleukin (IL)-1β in the brain. As young adults, these animals were more susceptible to lithium-pilocarpine and pentylenetetrazol-induced seizures and showed memory deficits in fear conditioning. Whereas there was no alteration in adult hippocampal cytokine levels, we found a marked increase in NMDA (NR2A and C) and AMPA (GluR1) glutamate receptor subunit mRNA expression. The increase in seizure susceptibility, glutamate receptor subunits, and hippocampal IL-1β levels were suppressed by neonatal systemic minocycline. Thus, a novel model of viral CNS inflammation reveals pathophysiological relationships between brain cytokines, glutamate receptors, behaviour and seizures, which can be attenuated by anti-inflammatory agents like minocycline.

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Microglial activation and TNFα production mediate altered CNS excitability following peripheral inflammation

Cited by 366 publications

References 64 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

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats

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