Role of the Fractalkine Receptor in CNS Autoimmune Inflammation: New Approach Utilizing a Mouse Model Expressing the Human CX3CR1

Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS) is the leading cause of non-traumatic neurological disability in young adults. Immune mediated destruction of myelin and oligodendrocytes is considered the primary pathology of MS, but progressive axonal loss is the major cause of neurological disability. In an effort to understand microglia function during CNS inflammation, our laboratory focuses on the fractalkine/CX3CR1 signaling as a regulator of microglia neurotoxicity in various models of neurodegeneration. Fractalkine (FKN) is a transmembrane chemokine expressed in the CNS by neurons and signals through its unique receptor CX3CR1 present in microglia. During experimental autoimmune encephalomyelitis (EAE), CX3CR1 deficiency confers exacerbated disease defined by severe inflammation and neuronal loss. The CX3CR1 human polymorphism I249/M280 present in ∼20% of the population exhibits reduced adhesion for FKN conferring defective signaling whose role in microglia function and influence on neurons during MS remains unsolved. The aim of this study is to assess the effect of weaker signaling through hCX3CR1I249/M280 during EAE. We hypothesize that dysregulated microglial responses due to impaired CX3CR1 signaling enhance neuronal/axonal damage. We generated an animal model replacing the mouse CX3CR1 locus for the hCX3CR1I249/M280 variant. Upon EAE induction, these mice exhibited exacerbated EAE correlating with severe inflammation and neuronal loss. We also observed that mice with aberrant CX3CR1 signaling are unable to produce FKN and ciliary neurotrophic factor during EAE in contrast to wild type mice. Our results provide validation of defective function of the hCX3CR1I249/M280 variant and the foundation to broaden the understanding of microglia dysfunction during neuroinflammation. © 2018 Cardona et al

Phenotypic features effectively stratify risk for advanced colorectal neoplasia in asymptomatic adults

poster abstractBackground: While colorectal cancer (CRC) screening is effective and cost-effective for reducing CRC incidence and mortality, it is underutilized (nearly 40% of U.S. adults are either not current with or have never been screened), inefficient (low-risk persons undergo colonoscopy), and costly to the U.S. health care system. A simple and effective way of stratifying risk for advanced neoplasia (AN – CRC and advanced, precancerous polyps) could improve the efficiency and uptake of screening by tailoring colonoscopy toward persons at highrisk and giving low-risk persons less-invasive options. Although several risk factors for AN have been identified, they are not used in clinical practice in part because of inability to integrate the factors to produce a risk estimate. Objective: To derive and validate a risk index for AN (CRC, advanced adenomas, serrated polyps >= 1 cm) anywhere in the colorectum. Methods: We measured socio-demographic features, medical and family history, lifestyle factors, and physical features in 50-80 year old persons who underwent first-time screening colonoscopy between December 2004 and September 2011, and linked these factors to endoscopic and histologic findings. Using logistic regression, we derived a risk equation on a randomly selected 2/3s of the sample. A 12-variable model was selected based on optimal statistical metrics. Based on model coefficients, we assigned points to each variable to create a risk score, which ranged from -13 to 8. Scores with comparable magnitudes of risk were collapsed into 3 risk categories. The model was tested on the remaining third of the sample. Results: Among 3025 subjects in the derivation set (mean age 57.3 ± 6.5 years; 52% women), the prevalence of AN was 9.4% (including 26 CRCs). Model variables include age, sex, smoking, ethanol use, marital status, NSAID and aspirin use, physical activity, education level, and metabolic syndrome (P-value for fit = 0.09; cstatistic=0.78). Respective risks of AN in the low- (scores of -13 to -5), intermediate- (scores of -4 to 2) and high- (scores of 3 to 12) were 1.52% (95%, 0.07-2.8%), 6.86%, and 26.8% (P-value for trend < 0.001), with respective cohort proportions of 23%, 59% and 18%. Ten low-risk subjects had AN (0 CRCs, 6 distal). Based on finding a distal sentinel polyp, sigmoidoscopy to the descending colon would have detected 7(70%) ANs. Among the 1475 subjects in the test set (mean age 57.2 ± 6.5 years; 52% women), AN prevalence was 8.4%. Risk of AN in the low-risk subgroup was 2.73% (CI, 1.25-5.11%) and was 5.57% and 25.4% in the intermediate- and high-risk subgroups, respectively (P<0.001), with cohort proportions of 23%, 59%, and 18%. Nine low-risk subjects had AN (0 CRCs, 5 distal, 6 detectable by sigmoidoscopy. Conclusion: This new risk index effectively stratifies the risk for AN among asymptomatic adults, identifying a low-risk subgroup of 23% that may be screened effectively and efficiently with tests other than colonoscopy and a high-risk subgroup of 18% in which colonoscopy may be preferable. If validated in other settings, this index could increase both the efficiency and uptake of CRC screening

Human Brain Microvascular Endothelial Cells and Umbilical Vein Endothelial Cells Differentially Facilitate Leukocyte Recruitment and Utilize Chemokines for T Cell Migration

Endothelial cells that functionally express blood brain barrier (BBB) properties are useful surrogates for studying leukocyte-endothelial cell interactions at the BBB. In this study, we compared two different endothelial cellular models: transfected human brain microvascular endothelial cells (THBMECs) and human umbilical vein endothelial cells (HUVECs). With each grow under optimal conditions, confluent THBMEC cultures showed continuous occludin and ZO-1 immunoreactivity, while HUVEC cultures exhibited punctate ZO-1 expression at sites of cell-cell contact only. Confluent THBMEC cultures on 24-well collagen-coated transwell inserts had significantly higher transendothelial electrical resistance (TEER) and lower solute permeability than HUVECs. Confluent THBMECs were more restrictive for mononuclear cell migration than HUVECs. Only THBMECs utilized abluminal CCL5 to facilitate T-lymphocyte migration in vitro although both THBMECs and HUVECs employed CCL3 to facilitate T cell migration. These data establish baseline conditions for using THBMECs to develop in vitro BBB models for studying leukocyte-endothelial interactions during neuroinflammation

How can polygenic inheritance be used in population screening for common diseases?

Advances in genomics have near-term impact on diagnosis and management of monogenic disorders. For common complex diseases, the use of genomic information from multiple loci (polygenic model) is generally not useful for diagnosis and individual prediction. In principle, the polygenic model could be used along with other risk factors in stratified population screening to target interventions. For example, compared to age-based criterion for breast, colorectal, and prostate cancer screening, adding polygenic risk and family history holds promise for more efficient screening with earlier start and/or increased frequency of screening for segments of the population at higher absolute risk than an established screening threshold; and later start and/or decreased frequency of screening for segments of the population at lower risks. This approach, while promising, faces formidable challenges for building its evidence base and for its implementation in practice. Currently, it is unclear whether or not polygenic risk can contribute enough discrimination to make stratified screening worthwhile. Empirical data are lacking on population-based age-specific absolute risks combining genetic and non-genetic factors, on impact of polygenic risk genes on disease natural history, as well as information on comparative balance of benefits and harms of stratified interventions. Implementation challenges include difficulties in integration of this information in the current health-care system in the United States, the setting of appropriate risk thresholds, and ethical, legal, and social issues. In an era of direct-to-consumer availability of personal genomic information, the public health and health-care systems need to prepare for an evidence-based integration of this information into population screening

Tailoring Colorectal Cancer Screening by Considering Risk of Advanced Proximal Neoplasia

Quantifying risk of advanced proximal colorectal neoplasia might allow tailoring of colorectal cancer screening, with colonoscopy for those at high risk, and less invasive screening for very low-risk persons

A novel role for microglia in minimizing excitotoxicity

Microglia are the abundant, resident myeloid cells of the central nervous system (CNS) that become rapidly activated in response to injury or inflammation. While most studies of microglia focus on this phenomenon, little is known about the function of 'resting' microglia, which possess fine, branching cellular processes. Biber and colleagues, in a recent paper in Journal of Neuroinflammation, report that ramified microglia can limit excitotoxicity, an important insight for understanding mechanisms that limit neuron death in CNS disease

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Does It Matter Who Writes Medical News Stories?

David Henry and colleagues review Australian news stories over a five-year period to assess whether quality is associated with who wrote the story: a specialist health journalist or a non-specialist