GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis

Galli, Edoardo; Hartmann, Felix J.; Schreiner, Bettina; Ingelfinger, Florian; Arvaniti, Eirini; Diebold, Martin; Mrdjen, Dunja; Meer, Franziska van der; Krieg, Carsten; Nimer, Faiez Al; Sanderson, Nicholas; Stadelmann, Christine; Khademi, Mohsen; Piehl, Fredrik; Claassen, Manfred; Derfuss, Tobias; Olsson, Tomas; Becher, Burkhard

doi:10.1038/s41591-019-0521-4

Cited by 144 publications

(160 citation statements)

References 69 publications

(76 reference statements)

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“…Further, IL‐17 and TNFα increased VCAM1 transcript in brain stem compared to spinal cord astrocytes (Figure 2c), while IFNγ highly upregulated CXCR7 in spinal cord astrocytes compared to those from the brain stem (Figure 2d). While granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is also known to contribute to inflammation during EAE and MS (Galli et al, ; Kroenke et al, ; Pierson & Goverman, ; Rothhammer et al, ), we did not observe a significant regional difference in VCAM1 transcripts in astrocytes following GM‐CSF treatment (data not shown).…”

Section: Resultscontrasting

confidence: 59%

Astrocyte‐T cell crosstalk regulates region‐specific neuroinflammation

Williams

Manivasagam

Smith

et al. 2020

Glia

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During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions. While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood. Here, we demonstrate that astrocytes exhibit region-specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation. Analysis of cytokine receptor expression in human astrocytes showed region-specific responsiveness to Th1 and Th17 inflammatory cytokines. Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM-1 and CXCR7 that is both cytokine and CNS region-specific. Using in vivo models of spinal cord versus brain stem trafficking of myelin-specific T cells and astrocyte-specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM-1 and CXCR7 in these locations. Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region-and cytokine-specific modulation of localizing cue expression by astrocytes. These findings identify a role for inflammatory cytokines in mediating local astrocyte-dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation.astrocyte, CXCR7, cytokine, neuroinflammation, regional heterogeneity, T cell, VCAM-1 Jessica L. Williams and Sindhu Manivasagam contributed equally to this study.

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Section: Resultscontrasting

confidence: 59%

Astrocyte‐T cell crosstalk regulates region‐specific neuroinflammation

Williams

Manivasagam

Smith

et al. 2020

Glia

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“…Granulocyte-macrophage colony-simulating factor (GM-CSF), originally identified as a hematopoietic growth factor has been recently identified as a prominent factor playing role in inflammation and autommunity [44,45]. This cytokine apparently plays an important role in the pathogenesis of MS, especially in modulation of myeloid cell function and potentially direct triggering of tissue destruction by these cells [46]. In our study, GM-CSF showed the most robust correlations with the lipoprotein subfractions, confirming its supposed role in the pathogenesis of MS.…”

Section: Discussionmentioning

confidence: 99%

Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?

et al. 2020

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Background: Inflammatory cytokines contribute to proatherogenic changes in lipid metabolism by reduction of HDLcholesterol (HDL-C) levels, impairment of its antiinflammatory and antioxidant functions. Therefore, the protective actions of HDL-C can be limited in chronic inflammatory diseases such as multiple sclerosis (MS). The aim of this study was to assess the association between lipoprotein subfractions and inflammatory status in early stages of multiple sclerosis.Methods: Polyacrylamide gel electrophoresis Lipoprint© System was used for lipoprotein profile analysis in 19 newly diagnosed MS patients, and in matched 19 healthy controls. Serum levels of interleukin (IL) 1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor, interferon-γ and TNF-α were measured by multiplex bead assay. Results: Concentrations of the measured cytokines and lipoprotein subclasses were comparable between MS patients and controls. Male, but not female MS patients had significantly higher total HDL-C and small HDL-C subfraction than healthy controls. Large HDL-C negatively correlated with all measured cytokines except IL-17 in MS but not in controls.Intermediate HDL-C subfractions correlated positively with all measured cytokines except G-CSF in MS females but not in MS males or controls. Conclusion:Our results of higher HDL-C and mainly its small HDL-C subfraction suggest that male MS patients are at higher risk of atherosclerosis and the subtle dyslipidemia is present in early stages of the disease. The correlations between specific HDL-C subfractions and the inflammatory cytokines demonstrate mutual links between systemic inflammation and lipid metabolism in MS.

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“…S1. First, we performed an unbiased discovery approach with CellCnn, a neural network-based artificial intelligence algorithm allowing analysis of single-cell data and detection of cells associated with clinical status (28)(29)(30). During training, CellCnn learns combinations of weights for each marker in a given panel that best discriminate between groups of patients.…”

Section: Sars-cov2 Induces Phenotypic Changes In Circulating Immune Cmentioning

confidence: 99%

Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome

Roussel

Ferrant

Reizine

et al. 2020

Preprint

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Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite recent immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown, To address this question, we built 3 cohorts of patients categorized in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells was specifically found in COVID-19posARDSpos, unlike COVID-19negARDSpos patients. Moreover, this signature was shared by COVID-19posARDSneg patients, suggesting severe COVID-19 patients, whatever they experienced or not ARDS, displayed similar immune dysfunctions. We also showed an increase in CD14posHLA-DRlow and CD14lowCD16pos monocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management.

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GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis

Cited by 144 publications

References 69 publications

Astrocyte‐T cell crosstalk regulates region‐specific neuroinflammation

Astrocyte‐T cell crosstalk regulates region‐specific neuroinflammation

Lipoprotein profiling in early multiple sclerosis patients: effect of chronic inflammation?

Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome

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