Regulation of Toll-Like Receptors in the Choroid Plexus in the Immature Brain After Systemic Inflammatory Stimuli

Stridh, Linnea; Ek, C. Joakim; Wang, Xiaoyang; Nilsson, Holger; Mallard, Carina

doi:10.1007/s12975-012-0248-8

Cited by 39 publications

(42 citation statements)

References 42 publications

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“…In addition to its important roles in host defense in clearing bacteria, TLR2 may mediate some forms of inflammatory brain injury [42], including middle cerebral artery occlusion [43] and neonatal hypoxia-ischemiainduced brain injury [44]. Indeed, consistent with the known role of TLR2 in mediating neuroinflammation and neuronal damage [45], we have previously demonstrated that a single intraperitoneal injection of the TLR2 agonist Pam 3 CSK 4 revealed a robust increase in the WBC count in the CSF in mice on PND8 [38], and repeated administration of Pam 3 CSK 4 induced brain injury in newborn animals [19]. S. epidermidis bacteremia induced TLR2 expression in the brain in our current study ( Figure 5).…”

Section: Discussionmentioning

confidence: 62%

“…Of note, functional inhibition of CCL2 by using a neutralizing antibody protects the neonatal rat brain from acute excitotoxic injury [37]. As there was a significant increase in leukocyte numbers in the CSF 6 hours after S. epidermidis, similar in magnitude to that observed after intraperitoneal injection of lipopolysaccharide (0.3 mg/kg) [38], there is apparently recruitment of cells across the choroid plexus early after S. epidermidis injection, which might contribute to CCL2 production in the brain and subsequent impaired brain development.…”

Section: Discussionmentioning

confidence: 77%

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Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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Background. Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.Methods. Wild-type and TLR2-deficient (TLR2−/−) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.Results. Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2−/− mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.Conclusions. Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 77%

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

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“…This differential expression potentially allows for the detection of many bacterial and viral components, mediating the responses necessary for the elimination of invading microorganisms, thereby protecting the brain. However, there are also data that demonstrate that infectious and non-infectious endogenous stimuli may be associated with a disturbance of BCSFB function (Marques et al, 2009a, b;Schwerk et al, 2010;Stridh et al, 2013). Marques et al (2009a, b) showed an altered gene expression profile in the CP of mice after peripheral administration of LPS, including the up-regulation of genes implicated in acute phase reactions and extracellular matrix remodelling, as well as the down-regulation of genes involved in the maintenance of BCSFB function.…”

Section: Discussionmentioning

confidence: 99%

Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes

Skipor

Szczepkowska

Kowalewska

et al. 2015

Acta Veterinaria Hungarica

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The blood-cerebrospinal fluid barrier (BCSFB) located in the epithelial cells of the choroid plexus (CP) forms the interface between the cerebrospinal fluid (CSF) and pathogen components circulating in the blood. The CP is also implicated in the passage of peripheral immune signals and circulation of immune cells into the central nervous system. Toll-like receptors (TLRs) are patternrecognition receptors that play a crucial role in the recognition of pathogens and triggering of the innate immune response. In sheep, ten members of the TLR family have been identified and cloned. We used real-time PCR analyses to examine the profiles of TLR mRNA expression in the CP of cerebral ventricles in healthy adult ewes. The transcripts for all ten TLRs except TLR8 were present; however, we observed a high variation in the degree of expression of the TLR5 and TLR1 genes (coefficient of variation: 61% and 46%, respectively) as well as a moderate variation in the expression of the TLR4 (34%), TLR2 (27%) and TLR6 (26%) genes. The TLR9, TLR7, TLR3 and TLR10 genes were the four receptors with relatively invariable expression levels (coefficient of variation: 7%, 8%, 16% and 17%, respectively) across the six adult ewes. The concentration of cortisol in blood collected prior to sacrificing the ewes ranged from 0.18 to 78.9 ng/ml. There was no correlation between cortisol concentration and mRNA expression of any of the examined TLRs. These data suggest that the CP has the potential to sense the presence of many bacterial and viral components and mediate responses for the elimination of invading microorganisms, thereby protecting the brain.

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“…In neurological disorders as different as brain trauma [155], perinatal inflammation triggered by bacterial components [151], and experimental autoimmune encephalomyelitis (EAE) [41], the balanced cytokine and chemokine milieu within the choroid plexuses changes rapidly and may thus directly contribute to altered immune cell activation and their subsequent trafficking across the inflamed BCSFB into the CNS. Increased numbers of T cells and B cells are found in the CSF of patients with CNS infections or multiple sclerosis [3,16].…”

Section: Neuroimmune Function Of the Choroid Plexuses In Neurologicalmentioning

confidence: 99%

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

et al. 2018

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The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the developing and adult brain, and CSF compartments are key to the immune surveillance of the CNS. In these contexts, the choroid plexuses are an important source of biologically active molecules involved in brain development, stem cell proliferation and differentiation, and brain repair. By sensing both physiological changes in brain homeostasis and peripheral or central insults such as inflammation, they also act as sentinels for the CNS. Finally, their role in the control of immune cell traffic between the blood and the CSF confers on the choroid plexuses a function in neuroimmune regulation and implicates them in neuroinflammation. The choroid plexuses, therefore, deserve more attention while investigating the pathophysiology of CNS diseases and related comorbidities.

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Regulation of Toll-Like Receptors in the Choroid Plexus in the Immature Brain After Systemic Inflammatory Stimuli

Cited by 39 publications

References 42 publications

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Profile of toll-like receptor mRNA expression in the choroid plexus in adult ewes

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

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