Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective ...treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages.
Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that ...astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate
that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, ...effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.
Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple ...sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
Abstract
The programmed cell death protein 1/programmed cell death ligand 1 axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases, while ...its role in multiple sclerosis is unclear. Here, we aimed to analyse expression patterns of programmed cell death protein 1 and programmed cell death ligand 1 on peripheral blood mononuclear cells and their soluble variants in multiple sclerosis patients and controls, to determine their correlation with clinical disability and disease activity. In a cross-sectional study, we performed in-depth flow cytometric immunophenotyping of peripheral blood mononuclear cells and analysed soluble programmed cell death protein 1 and programmed cell death ligand 1 serum levels in patients with relapsing–remitting multiple sclerosis and controls. In comparison to control subjects, relapsing–remitting multiple sclerosis patients displayed distinct cellular programmed cell death protein 1/programmed cell death ligand 1 expression patterns in immune cell subsets and increased soluble programmed cell death ligand 1 levels, which correlated with clinical measures of disability and MRI activity over time. This study extends our knowledge of how programmed cell death protein 1 and programmed cell death ligand 1 are expressed in the membranes of patients with relapsing–remitting multiple sclerosis and describes for the first time the elevation of soluble programmed cell death ligand 1 in the blood of multiple sclerosis patients. The distinct expression pattern of membrane-bound programmed cell death protein 1 and programmed cell death ligand 1 and the correlation between soluble programmed cell death ligand 1, membrane-bound programmed cell death ligand 1, disease and clinical factors may offer therapeutic potential in the setting of multiple sclerosis and might improve future diagnosis and clinical decision-making.
Tsaktanis et al. reveal distinct expression patterns of membrane-bound and soluble programmed cell death ligand 1 in relapsing–remitting multiple sclerosis, correlating with disease severity. These findings demonstrate regulation of programmed cell death protein 1/programmed cell death ligand 1 signalling and emphasize its potential as a disease surveillance and therapeutic target.
Graphical Abstract
Graphical Abstract
BackgroundThe Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing ...smoking, but may have unintended consequences related to weight gain.MethodsWeight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.4 to 15.8 mg/g or their own usual brand for 6 weeks. Additional analyses evaluated weight gain in the lowest nicotine content cigarette groups (0.4 and 0.4 mg/g, high tar) to examine the effect of study product in compliant participants as assessed by urinary biomarkers. Differences in outcomes due to gender were also explored.FindingsThere were no significant differences in weight gain when comparing the reduced nicotine conditions with the 15.8 mg/g control group across all treatment groups and weeks. However, weight gain at week 6 was negatively correlated with nicotine exposure in the 2 lowest nicotine content cigarette conditions. Within the 2 lowest nicotine content cigarette conditions, male and female smokers biochemically verified to be compliant on study product gained significantly more weight than non-compliant smokers and control groups.ConclusionsThe effect of random assignment to investigational cigarettes with reduced nicotine on weight gain was likely obscured by non-compliance with study product. Men and women who were compliant in the lowest nicotine content cigarette conditions gained 1.2 kg over 6 weeks, indicating weight gain is a likely consequence of reduced exposure to nicotine.Trial registration numberNCT01681875, Post-results.
Patients who use cannabis for medical reasons may benefit from discussions with clinicians about health risks of cannabis and evidence-based treatment alternatives. However, little is known about the ...prevalence of medical cannabis use in primary care and how often it is documented in patient electronic health records (EHR).
To estimate the primary care prevalence of medical cannabis use according to confidential patient survey and to compare the prevalence of medical cannabis use documented in the EHR with patient report.
This study is a cross-sectional survey performed in a large health system that conducts routine cannabis screening in Washington state where medical and nonmedical cannabis use are legal. Among 108 950 patients who completed routine cannabis screening (between March 28, 2019, and September 12, 2019), 5000 were randomly selected for a confidential survey about cannabis use, using stratified random sampling for frequency of past-year use and patient race and ethnicity. Data were analyzed from November 2020 to December 2021.
Survey measures of patient-reported past-year cannabis use, medical cannabis use (ie, explicit medical use), and any health reason(s) for use (ie, implicit medical use).
Survey data were linked to EHR data in the year before screening. EHR measures included documentation of explicit and/or implicit medical cannabis use. Analyses estimated the primary care prevalence of cannabis use and compared EHR-documented with patient-reported medical cannabis use, accounting for stratified sampling and nonresponse.
Overall, 1688 patients responded to the survey (34% response rate; mean SD age, 50.7 17.5 years; 861 female 56%, 1184 White 74%, 1514 non-Hispanic 97%, and 1059 commercially insured 65%). The primary care prevalence of any past-year patient-reported cannabis use on the survey was 38.8% (95% CI, 31.9%-46.1%), whereas the prevalence of explicit and implicit medical use were 26.5% (95% CI, 21.6%-31.3%) and 35.1% (95% CI, 29.3%-40.8%), respectively. The prevalence of EHR-documented medical cannabis use was 4.8% (95% CI, 3.45%-6.2%). Compared with patient-reported explicit medical use, the sensitivity and specificity of EHR-documented medical cannabis use were 10.0% (95% CI, 4.4%-15.6%) and 97.1% (95% CI, 94.4%-99.8%), respectively.
These findings suggest that medical cannabis use is common among primary care patients in a state with legal use, and most use is not documented in the EHR. Patient report of health reasons for cannabis use identifies more medical use compared with explicit questions about medical use.
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