Systemic inflammation induces axon injury during brain inflammation

ABSTRACTSystemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.

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Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation

Frontiers in Immunology ◽

10.3389/fimmu.2020.614509 ◽

2020 ◽

Vol 11 ◽

Author(s):

Maximilian Lenz ◽

Amelie Eichler ◽

Pia Kruse ◽

Andreas Strehl ◽

Silvia Rodriguez-Rozada ◽

...

Keyword(s):

Synaptic Plasticity ◽

Systemic Inflammation ◽

Magnetic Stimulation ◽

Long Term Potentiation ◽

Interleukin 10 ◽

Brain Inflammation ◽

Tissue Cultures ◽

Brain Functions ◽

Repetitive Magnetic Stimulation ◽

Excitatory Neurotransmission

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.

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Pertussis toxin–induced inflammatory response exacerbates intracerebral haemorrhage and ischaemic stroke in mice

Stroke and Vascular Neurology ◽

10.1136/svn-2021-000987 ◽

2021 ◽

pp. svn-2021-000987

Author(s):

Ming Zou ◽

Yan Feng ◽

Yuwhen Xiu ◽

Yan Li ◽

Ying Zhang ◽

...

Keyword(s):

Brain Injury ◽

Inflammatory Response ◽

Mouse Model ◽

Ischaemic Stroke ◽

Systemic Inflammation ◽

Pertussis Toxin ◽

Intracerebral Haemorrhage ◽

Brain Inflammation ◽

Neurological Deficits ◽

Stroke Severity

BackgroundStroke is a devastating disease, including intracerebral haemorrhage (ICH) and ischaemic stroke. Emerging evidences indicate that systemic inflammatory cascades after stroke contribute to brain damage. However, the direct effects and features of systemic inflammation on brain injury, especially comparing between ischaemic and haemorrhagic stroke, are still obscure.MethodsPertussis toxin (PT) was used to build a pro-inflammatory milieu after ICH and ischaemic stroke in mouse model. The neurodeficits, stroke lesion, immune response and blood–brain barrier (BBB) destruction were assessed.ResultsIn ICH mouse model, PT-induced systemic inflammation exacerbated neurological deficits, and enlarged haemorrhage lesion and perihaematomal oedema. We also found promoted leucocyte infiltration and inflammatory cytokine release into the brain after PT treatment. Moreover, the integrity of the BBB was further disrupted after receiving PT. Furthermore, we demonstrated that PT enhanced brain inflammation and aggravated stroke severity in middle cerebral artery occlusion mouse model.ConclusionsOur results suggest that PT increases inflammatory response that exacerbates brain injury after ICH or ischaemic stroke in mouse model.

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Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

Neural Plasticity ◽

10.1155/2018/7692182 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Efrat Shavit Stein ◽

Marina Ben Shimon ◽

Avital Artan Furman ◽

Valery Golderman ◽

Joab Chapman ◽

...

Keyword(s):

Systemic Inflammation ◽

Specific Inhibitor ◽

Coagulation Factor ◽

Coagulation Factors ◽

Brain Inflammation ◽

Coagulation Activity ◽

Microglia Cell ◽

The Brain

Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 ± 0.15 mU/mg versus 0.2 ± 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real-time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 ± 0.6- and 2.3 ± 0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFα, CXL9, and CCL1; p<0.006) and coagulation responses (FX and PAR1; p<0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival.

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Exposure to Urban Air Pollution and Bone Health in Clinically Healthy Six-year-old Children

Archives of Industrial Hygiene and Toxicology ◽

10.2478/10004-1254-64-2013-2219 ◽

2013 ◽

Vol 64 (1) ◽

pp. 23-34 ◽

Cited By ~ 19

Author(s):

Lilian Calderón-Garcidueñas ◽

Antonieta Mora-Tiscareño ◽

Maricela Francolira ◽

Ricardo Torres-Jardón ◽

Bernardo Peña-Cruz ◽

...

Keyword(s):

Vitamin D ◽

Air Pollution ◽

Bone Mass ◽

Systemic Inflammation ◽

Inflammatory Markers ◽

Urban Air Pollution ◽

Brain Inflammation ◽

Urban Air ◽

Mineral Density ◽

The Impact

Air pollution induces systemic inflammation, as well as respiratory, myocardial and brain inflammation in children. Peak bone mass is influenced by environmental factors. We tested the hypothesis that six-year-olds with lifetime exposures to urban air pollution will have alterations in inflammatory markers and bone mineral density (BMD) as opposed to low-polluted city residents when matched for BMI, breast feeding history, skin phototype, age, sex and socioeconomic status. This pilot study included 20 children from Mexico City (MC) (6.17 years ± 0.63 years) and 15 controls (6.27 years ± 0.76 years). We performed full paediatric examinations, a history of outdoor exposures, seven-day dietary recalls, serum inflammatory markers and dual-energy X-ray absorptiometry (DXA). Children in MC had significantly higher concentrations of IL-6 (p=0.001), marked reductions in total blood neutrophils (p= 0.0002) and an increase in monocytes (p=0.005). MC children also had an insufficient Vitamin D intake and spent less time outdoors than controls (p<0.001) in an environment characterized by decreased UV light, with ozone and fine particulates concentrations above standard values. There were no significant differences between the cohorts in DXA Z scores. The impact of systemic inflammation, vitamin D insufficiency, air pollution, urban violence and poverty may have long-term bone detrimental outcomes in exposed paediatric populations as they grow older, increasing the risk of low bone mass and osteoporosis. The selection of reference populations for DXA must take into account air pollution exposures.

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