Objective- Dyslipidemia is a component of the metabolic syndrome, an established risk factor for atherosclerotic cardiovascular disease, and is also observed in various autoimmune and chronic ...inflammatory conditions. However, there are limited opportunities to study the impact of acquired dyslipidemia on cardiovascular and immune pathology. Approach and Results- We designed a model system that allows for the conversion to a state of acute hyperlipidemia in adult life, so that the consequences of such a transition could be observed, through conditionally deleting APOE (apolipoprotein E) in the adult mouse. The transition to hypercholesterolemia was accompanied by adaptive immune responses, including the expansion of T lymphocyte helper cell 1, T follicular helper cell, and T regulatory subsets and the formation of germinal centers. Unlike steady-state Apoe
mice, abrupt loss of APOE induced rapid production of antibodies recognizing rheumatoid disease autoantigens. Genetic ablation of the germinal center reduced both autoimmunity and atherosclerosis, indicating that the immune response that follows loss of APOE is independent of atherosclerosis but nevertheless promotes plaque development. Conclusions- Our findings suggest that immune activation in response to hyperlipidemia could contribute to a wide range of inflammatory autoimmune diseases, including atherosclerosis.
Retinal cells within neurovascular units generate the blood–retinal barrier (BRB) to regulate the local retinal microenvironment and to limit access to inflammatory cells. Breakdown of the ...endothelial junctional complexes in the BRB negatively affects neuronal signaling and ultimately causes vision loss. As new therapeutics are being developed either to prevent barrier disruption or to restore barrier function, access to physiologically relevant human in vitro tissue models that recapitulate important features of barrier biology is essential for disease modeling, target validation, and toxicity assessment. Here, a tunable organ‐on‐a‐chip model of the retinal microvasculature using human retinal microvascular endothelial cells with integrated flow is described. Automated imaging and image analysis methods are employed for facile screening of leakage mediators and cytokine inhibitors on barrier properties. The developed retinal microvasculature‐on‐a‐chip will enable improved understanding of BRB biology and provide an additional tool for drug discovery.
A human retinal microvasculature‐on‐a‐chip for use in drug discovery is presented here. This 3D model, with support matrix and integrated flow, displays tight endothelial barrier function, not observed with the same cells in 2D. Biologically relevant response with exposure to leakage mediators relevant to human disease is observed. The platform, designed in a multi‐well format, enables rapid screening of anti‐permeability therapeutics.
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•An overview of material properties that guide stem cell fate is provided.•The role of high throughput screening for the discovery of materials.•Fabrication of two and ...three-dimensional screening platforms for cellular interfacing.•Non-exhaustive summary of stem-cell substrates identified from screens.•Technological hurdles for high throughput materials and cellular characterization.
Insights into the complex stem cell niche have identified the cell–material interface to be a potent regulator of stem cell fate via material properties such as chemistry, topography and stiffness. In light of this, materials scientists have the opportunity to develop bioactive materials for stem cell culture that elicit specific cellular responses. To accelerate materials discovery, high throughput screening platforms have been designed which can rapidly evaluate combinatorial material libraries in two and three-dimensional environments. In this review, we present screening platforms for the discovery of material properties that influence stem cell behavior.
Although PD-1 was shown to be a hallmark of T cells exhaustion, controversial studies have been reported on the role of PD-1 on NK cells. Here, we found by flow cytometry and single cell RNA ...sequencing analysis that PD-1 can be expressed on MHC class I-deficient tumor-infiltrating NK cells in vivo. We also demonstrate distinct alterations in the phenotype of PD-1-deficient NK cells and a more mature phenotype which might reduce their capacity to migrate and kill in vivo. Tumor-infiltrating NK cells that express PD-1 were highly associated with the expression of CXCR6. Furthermore, our results demonstrate that PD-L1 molecules in membranes of PD-1-deficient NK cells migrate faster than in NK cells from wild-type mice, suggesting that PD-1 and PD-L1 form cis interactions with each other on NK cells. These data demonstrate that there may be a role for the PD-1/PD-L1 axis in tumor-infiltrating NK cells in vivo.
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•NK cells from PD-1 deficient mice have a more mature phenotype•Elimination of MHC-I-deficient cells is impaired in PD-1−/− mice•PD-1 expression on NK cells is associated with surface expression of CXCR6•PD-1/PD-L1 interactions on NK cells may occur in cis
Immunology; Components of the immune system; Cancer; Transcriptomics
Asthma is a complex disease of the airways primarily mediated by T helper 2 cells and innate lymphoid type 2 cells (Licona et al.,2013). Mice do not develop spontaneous asthma and therefore models ...have been developed for the assessment of key processes that underlie human pathology (Nial et al.,2008). Exposure to House Dust Mite (HDM) extract induces many key features of acute airway inflammation including elevated IgE levels, eosinophilia, goblet cell metaplasia, epithelial hypertrophy and airway hyperresponsiveness (AHR) in response to methacholine (Hammad et al., 2009; Dullaers et al., 2012; Coquet et al., 2015). The exact dose and duration of exposure to HDM can affect the type and extent of inflammation. In our case, we start with a low sensitizing dose that is increased on challenge, while others use differing schedules or a higher antigen concentration during sensitization of mice (Hondowicz et al., 2016; Trompette et al., 2014; Zaiss et al., 2015). We believe that using a low sensitizing dose more accurately separates the primary and secondary immune responses and reduces the possibility that HDM given during sensitization continues to fuel the immune response during challenge (Coquet et al., 2015; Plantinga et al., 2013). Here, we outline in text, pictures and video how to administer HDM extracts or cytokines via the intranasal route and briefly touch upon the subsequent analysis of inflammation in the airways covered otherwise in ( Han et al., 2013).
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