The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia

Predominance of Th2 polarization by Vitamin D through a STAT6-dependent mechanism

<p>Abstract</p> <p>Background</p> <p>Vitamin D has several reported immunomodulatory properties including the reduced generation of pro-inflammatory CD4+ T helper 1 (Th1) cells and the increase in levels of the anti-inflammatory Th2 subset. Less clear has been the impact of vitamin D on the pro-inflammatory Th17 subset, and whether and how vitamin D may preferentially drive the polarization of one of the T helper subsets.</p> <p>Methods</p> <p>Using human peripheral blood-derived mononuclear cells and mouse splenocytes and lymph node cells in culture, we examined whether and how vitamin D preferentially skews T cells towards the Th1, Th2 or Th17 subsets. Mice afflicted with the multiple sclerosis-like condition, experimental autoimmune encephalomyelitis (EAE), were examined in vivo for the relevance of the tissue culture-derived results.</p> <p>Results</p> <p>We report that the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 {1,25(OH)2D3}, consistently generates human and murine Th2 cells in culture, frequently leaving unchanged the levels of Th1/Th17 cytokines. As a result, the ratio of Th2 to Th1 and Th17 is increased by 1,25(OH)2D3. The upregulation of Th2 to Th1 or Th17 subsets by 1,25(OH)2D3 is enabled by an increase of the GATA-3 transcription factor, which itself is promoted upstream by an elevation of the STAT6 transcription factor. In mice, the alleviation of EAE severity by 1,25(OH)2D3 is accompanied by elevation of levels of GATA-3 and STAT6. Significantly, the efficacy of 1,25(OH)2D3 in ameliorating EAE is completely lost in mice genetically deficient for STAT6, which was accompanied by the inability of 1,25(OH)2D3 to raise GATA-3 in STAT6 null lymphocytes.</p> <p>Conclusions</p> <p>These results of vitamin D promoting a Th2 shift through upstream GATA-3 and STAT6 transcription factors shed mechanistic understanding on the utility of vitamin D in MS.</p

Understanding the roles of glia and circulating leukocytes in neurodegenerative diseases

https://www.frontiersin.org/research-topics/11664/understanding-the-roles-of-glia-and-circulating-leukocytes-in-neurodegenerative-disease

Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases

Aim: Minocycline has neuroprotective activities in several models of neurological disorders including spinal cord injury (SCI) where it prevents axonal loss and improves functional recovery. There are still gaps of knowledge on minocycline in SCI including whether it ameliorates neuronal loss at the focal site of trauma, and whether minocycline reduces the activity of matrix metalloproteinases (MMPs), a family of enzymes implicated in the pathophysiology of SCI. This study addressed these gaps. Methods: Mice were treated with either minocycline or vehicle control after a spinal cord contusion. MMPs were compared between the two groups using real time polymerase chain reaction and zymography. Immunohistochemistry was used to examine microglial activation and neuronal cell death. Results: While several MMP members were elevated in the spinal cord following injury, treatment with minocycline did not affect their expression. Importantly, minocycline reduced the loss of neurons in the epicenter of damage to the spinal cord and in segments caudal and rostral to the injury. Conclusion: Despite the inability of minocycline to alter MMPs, the results of neuroprotection at the lesion site support the continued testing of minocycline as a neuroprotective medication in experimental and clinical SCI

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination.

Background: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Methods: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 (EXTL2)-/- mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. Results: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genomewide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2-/- mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2-/- mice had exacerbated axonal damage and myelin disruption relative to wildtype mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow derived macrophages from EXTL2-/- mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). Conclusions: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.Canadian Institutes of Health Sciences Alberta/Novartis Translational Research Fund Multiple Sclerosis Society of Canad

Efficacy of Minocycline in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Rodent and Clinical Studies

Objectives: This study aimed to assess the efficacy of minocycline for the treatment of acute ischemic stroke.Background: While there have been meta-analysis that surveyed the efficacy of minocycline in the treatment of acute stroke, they have some methodological limitations. We performed a new systematic review which was distinct from previous one by adding new outcomes and including new studies.Methods: Document retrieval was executed through PubMed, Cochrane Central Register of Controlled Trials, the Stroke Center, NIH's Clinical Trials, Current Controlled Trials, and the WHO International Clinical Trials Registry Platform Search Portal before Jan 2018. The data meeting the inclusion criteria were extracted. Before meta-analysis, publication bias and heterogeneity of included studies were surveyed. Random and fixed-effects models were employed to calculate pooled estimates and 95% confidence intervals (CIs). Additionally, sensitivity and subgroup analyses were implemented.Result: For clinical studies, 4 trials with 201 patients in the minocycline group, and 195 patients in the control group met the inclusion criteria; 3 were randomized trials. At the end of 90-day follow up or discharge day, results showed that the groups receiving minocycline were superior to the control group, with significant differences in the NIHSS scores (mean difference [MD], −2.75; 95% CI, −4.78, 0.27; p = 0.03) and mRS scores (MD, −0.98; 95% CI, −1.27, −0.69; p &lt; 0.01), but not Barthel Index Score (MD, 9.04; 95% CI, −0.78, 18.07; p = 0.07). For rodent experiments, 14 studies were included. Neurological severity scores (NSS) was significantly improved (MD, −1.38; 95% CI, −1.64, −1.31; p &lt; 0.01) and infarct volume was obviously reduced (Std mean difference [SMD], −2.38; 95% CI, −3.40, −1.36; p &lt; 0.01) in the minocycline group. Heterogeneity among the studies was proved to exist for infarct volume (Chi2 = 116.12, p &lt; 0.01; I2 = 0.89) but not for other variables.Conclusions: Based on the results in our study, minocycline appears as an effective therapeutic option for acute ischemic stroke

Distinct characteristics and severity of brain magnetic resonance imaging lesions in women and men with multiple sclerosis assessed using verified texture analysis measures

Background and goalIn vivo characterization of brain lesion types in multiple sclerosis (MS) has been an ongoing challenge. Based on verified texture analysis measures from clinical magnetic resonance imaging (MRI), this study aimed to develop a method to identify two extremes of brain MS lesions that were approximately severely demyelinated (sDEM) and highly remyelinated (hREM), and compare them in terms of common clinical variables.MethodTexture analysis used an optimized gray-level co-occurrence matrix (GLCM) method based on FLAIR MRI from 200 relapsing-remitting MS participants. Two top-performing metrics were calculated: texture contrast and dissimilarity. Lesion identification applied a percentile approach according to texture values calculated: ≤ 25 percentile for hREM and ≥75 percentile for sDEM.ResultsThe sDEM had a greater total normalized volume yet smaller average size, and worse MRI texture than hREM. In lesion distribution mapping, the two lesion types appeared to overlap largely in location and were present the most in the corpus callosum and periventricular regions. Further, in sDEM, the normalized volume was greater and in hREM, the average size was smaller in men than women. There were no other significant results in clinical variable-associated analyses.ConclusionPercentile statistics of competitive MRI texture measures may be a promising method for probing select types of brain MS lesion pathology. Associated findings can provide another useful dimension for improved measurement and monitoring of disease activity in MS. The different characteristics of sDEM and hREM between men and women likely adds new information to the literature, deserving further confirmation

Fibrinogen in the glioblastoma microenvironment contributes to the invasiveness of brain tumor‐initiating cells

Glioblastomas (GBMs) are highly aggressive, recurrent, and lethal brain tumors that are maintained via brain tumor-initiating cells (BTICs). The aggressiveness of BTICs may be dependent on the extracellular matrix (ECM) molecules that are highly enriched within the GBM microenvironment. Here, we investigated the expression of ECM molecules in GBM patients by mining the transcriptomic databases and also staining human GBM specimens. RNA levels for fibronectin, brevican, versican, heparan sulfate proteoglycan 2 (HSPG2), and several laminins were high in GBMs compared to normal brain, and this was corroborated by immunohistochemistry. While fibrinogen transcript was at normal level in GBM, its protein immunoreactivity was prominent within GBM tissues. These ECM molecules in tumor specimens were in proximity to, and surrounding BTICs. In culture, fibronectin and pan-laminin induced the adhesion of BTICs onto the plastic substratum. However, fibrinogen increased the size of the BTIC spheres by facilitating the adhesive property, motility, and invasiveness of BTICs. These features of elevated invasiveness were corroborated in resected GBM specimens by the close proximity of fibrinogen with matrix metalloproteinase (MMP)-2 and-9, which are proteases implicated in metastasis. Moreover, the effect of fibrinogen-induced invasiveness was attenuated in BTICs where MMP-2 and -9 have been inhibited with siRNAs or pharmacological inhibitors. Our results implicate fibrinogen in GBM as a mediator of the invasive properties of BTICs, and as a target for therapy to reduce BTIC tumorigenecity

Anti-oxidant effects of cannabidiol relevant to intracerebral hemorrhage

Intracerebral hemorrhage (ICH) is a subtype of stroke with a high mortality rate. Oxidative stress cascades play an important role in brain injury after ICH. Cannabidiol, a major non-psychotropic phytocannabinoids, has drawn increasing interest in recent years as a potential therapeutic intervention for various neuropsychiatric disorders. Here we provide a comprehensive review of the potential therapeutic effects of cannabidiol in countering oxidative stress resulting from ICH. The review elaborates on the various sources of oxidative stress post-ICH, including mitochondrial dysfunction, excitotoxicity, iron toxicity, inflammation, and also highlights cannabidiol’s ability to inhibit ROS/RNS generation from these sources. The article also delves into cannabidiol’s role in promoting ROS/RNS scavenging through the Nrf2/ARE pathway, detailing both extranuclear and intranuclear regulatory mechanisms. Overall, the review underscores cannabidiol’s promising antioxidant effects in the context of ICH and suggests its potential as a therapeutic option