Brain, behavior, and immunity
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Brain Behav. Immun. · Mar 2015
Alterations in microglial phenotype and hippocampal neuronal function in transgenic mice with astrocyte-targeted production of interleukin-10.
Interleukin-10 (IL-10) is a cytokine classically linked with anti-inflammatory and protective functions in the central nervous system (CNS) in different neurodegenerative and neuroinflammatory conditions. In order to study the specific role of local CNS produced IL-10, we have created a new transgenic mouse line with astrocyte-targeted production of IL-10 (GFAP-IL10Tg). In the present study, the effects of local CNS IL-10 production on microglia, astrocytes and neuronal connectivity under basal conditions were investigated using immunohistochemistry, molecular biology techniques, electrophysiology and behavioural studies. ⋯ This study is the first description of a transgenic mouse with astrocyte-targeted production of the cytokine IL-10. The findings indicate that IL-10 induces a specific activated microglial phenotype concomitant with changes in hippocampal LTP responses. This transgenic animal will be a very useful tool to study IL-10 functions in the CNS, not only under basal conditions, but also after different experimental lesions or induced diseases.
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Brain Behav. Immun. · Mar 2015
Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome.
Traumatic brain injury (TBI) results in a significant inflammatory burden that perpetuates the production of inflammatory mediators and biomarkers. Interleukin-6 (IL-6) is a pro-inflammatory cytokine known to be elevated after trauma, and a major contributor to the inflammatory response following TBI. Previous studies have investigated associations between IL-6 and outcome following TBI, but to date, studies have been inconsistent in their conclusions. ⋯ Specifically, there was 70% concordance between those with TBI+polytrauma and the low TRAJ; in contrast, isolated TBI was similarly distributed between TRAJ groups. These data provide evidence that sustained, elevated levels of CSF IL-6 are associated with an increased inflammatory load, and these increases are associated with increased odds for unfavorable global outcomes in the first year following TBI. Future studies should explore additional factors contributing to IL-6 elevations, and therapies to mitigate its detrimental effects on outcome.
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Brain Behav. Immun. · Mar 2015
Alcohol-induced sedation and synergistic interactions between alcohol and morphine: a key mechanistic role for Toll-like receptors and MyD88-dependent signaling.
Increasing evidence demonstrates induction of proinflammatory Toll-like receptor (TLR) 2 and TLR4 signaling by morphine and, TLR4 signaling by alcohol; thus indicating a common site of drug action and a potential novel innate immune-dependent hypothesis for opioid and alcohol drug interactions. Hence, the current study aimed to assess the role of TLR2, TLR4, MyD88 (as a critical TLR-signaling participant), NF-κB, Interleukin-1β (IL-1β; as a downstream proinflammatory effector molecule) and the μ opioid receptor (MOR; as a classical site for morphine action) in acute alcohol-induced sedation (4.5g/kg) and alcohol (2.5g/kg) interaction with morphine (5mg/kg) by assessing the loss of righting reflex (LORR) as a measure of sedation. ⋯ In contrast, the interaction between morphine and alcohol was found to be MOR-, NF-κB-, TLR2- and MyD88-dependent, but did not involve TLR4 or Interleukin-1β. Morphine-alcohol interactions caused acute elevations in microglial cell counts and NF-κB-p65 positive cells in the motor cortex in concordance with wild-type and TLR2 deficient mouse behavioral data, implicating neuroimmunopharmacological signaling as a pivotal mechanism in this clinically problematic drug-drug interaction.
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Brain Behav. Immun. · Mar 2015
Stromal cell-derived CCL2 drives neuropathic pain states through myeloid cell infiltration in injured nerve.
Neuropathic pain resulting from peripheral nerve injury involves many persistent neuroinflammatory processes including inflammatory chemokines that control leukocyte trafficking and activate resident cells. Several studies have shown that CCL2 chemokine, a potent attractant of monocytes, and its cognate receptor, CCR2, play a critical role in regulating nociceptive processes during neuropathic pain. However, the role of CCL2 in peripheral leukocyte infiltration-associated neuropathic pain remains poorly understood. ⋯ Using a specific CCR2 antagonist and mice with a CCL2 genetic deletion, we have also established that the CCL2/CCR2 axis drives monocyte/macrophage infiltration and pain hypersensitivity in the CCI model. Finally, specific deletion of CCL2 in stromal or immune cells respectively using irradiated bone marrow-chimeric CCI mice demonstrated that stromal cell-derived CCL2 (in contrast to CCL2 immune cell-derived) tightly controls monocyte/macrophage recruitment into the lesion and plays a major role in the development of neuropathic pain. These findings demonstrate that in chronic pain states, CCL2 expressed by sciatic nerve cells predominantly drove local neuro-immune interactions and pain-related behavior through CCR2 signaling.
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Brain Behav. Immun. · Mar 2015
Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses.
Schizophrenia is associated with increased cardiovascular disease morbidity and mortality. Schizophrenia is also associated with immune and inflammatory abnormalities, including aberrant blood levels of lymphocytes, cytokines and high-sensitivity C-reactive protein (hsCRP). The purpose of this study is to investigate the relationship between total and differential white blood cell (WBC) counts, hsCRP, and indices of cardiovascular disease risk in patients with schizophrenia and related non-affective psychoses. 108 inpatients and outpatients age 18-70 with non-affective psychoses and 44 controls participated in this cross-sectional study. ⋯ In binary logistic regression analyses, total WBC count was a significant predictor of an elevated 10-year estimated risk of myocardial infarction and cardiovascular disease in subjects with non-affective psychosis (p⩽0.03 for each). Associations between total and differential WBC counts and cardiovascular disease risk indices were stronger in males than females with non-affective psychosis. Our findings provide further evidence that measurement of total and differential WBC counts may be germane to the clinical care of patients with schizophrenia and related disorders, and support an association between inflammation and cardiovascular disease risk in these patients.