CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice

Winkels, Holger; Meiler, Svenja; Lievens, Dirk; Engel, David; Spitz, Charlotte; Bürger, Christina; Beckers, Linda; Dandl, Angelika; Reim, Sigrid; Ahmadsei, Maiwand; Hartwig, Helene; Holdt, Lesca M.; Hristov, Michael; Megens, Remco T. A.; Schmitt, Martin; Biessen, E.A.L.; Borst, Jannie; Faußner, Alexander; Weber, Christian; Lutgens, Esther; Gerdes, Norbert

doi:10.1093/eurheartj/ehx517

Cited by 43 publications

(18 citation statements)

References 45 publications

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“…These CDs were also functional in leukocyte recruitment, cell-cell interaction, and slow rolling ( 80 – 90 ). The second group of five upregulated CDs, namely CD27 (a tumor necrosis factor receptor (TNFR), a superfamily member and co-stimulation receptor), semaphoring 7A (SEMA7A), CD108, (which promotes axonal growth and T cell development), TNFSF4 (CD134, OX40 ligand, a co-stimulation receptor), and GGT1[CD224, which promotes clear cell renal cell carcinoma initiation and progression ( 91 )], played roles in co-stimulating T cell immune responses, promoting cancer growth ( 92 ), and establishing immune memory ( 93 – 97 ). In addition, the third group of four inflammation-related CDs, such as MHC HLA-DR gamma chain (CD74) for MHC class II antigen presentation, interleukin-7 receptor (IL7R, which plays a critical role in the development of lymphocytes in a process called VDJ recombination), scavenger receptor class B, member 3 (CD36) for oxidized low-density lipoprotein (oxLDL) cell internalization ( 98 ), and toll-like receptor 3 (TLR3) for binding to double-stranded RNA/unmethylated CpG DNA and cooperating with scavenger receptor SREC-I to trigger inflammatory innate immune response ( 99 ), were dramatically upregulated in LPI-treated HAECs ( Figure 3B ) ( 100 – 103 ).…”

Section: Resultsmentioning

confidence: 99%

“…These CDs were also functional in leukocyte recruitment, cell-cell interaction, and slow rolling (80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90). The second group of five upregulated CDs, namely CD27 (a tumor necrosis factor receptor (TNFR), a superfamily member and co-stimulation receptor), semaphoring 7A (SEMA7A), CD108, (which promotes axonal growth and T cell development), TNFSF4 (CD134, OX40 ligand, a costimulation receptor), and GGT1[CD224, which promotes clear cell renal cell carcinoma initiation and progression (91)], played roles in co-stimulating T cell immune responses, promoting cancer growth (92), and establishing immune memory (93)(94)(95)(96)(97).…”

Section: Gpr55 a Specific Receptor For Lpis Is Expressed On The Endothelium Of Both Human And Mouse Aortas And Is Significantly Upregulatmentioning

confidence: 99%

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Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Xu¹,

Shao²,

Saaoud³

et al. 2021

Front. Cardiovasc. Med.

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To determine whether pro-inflammatory lipid lysophosphatidylinositols (LPIs) upregulate the expressions of membrane proteins for adhesion/signaling and secretory proteins in human aortic endothelial cell (HAEC) activation, we developed an EC biology knowledge-based transcriptomic formula to profile RNA-Seq data panoramically. We made the following primary findings: first, G protein-coupled receptor 55 (GPR55), the LPI receptor, is expressed in the endothelium of both human and mouse aortas, and is significantly upregulated in hyperlipidemia; second, LPIs upregulate 43 clusters of differentiation (CD) in HAECs, promoting EC activation, innate immune trans-differentiation, and immune/inflammatory responses; 72.1% of LPI-upregulated CDs are not induced in influenza virus-, MERS-CoV virus- and herpes virus-infected human endothelial cells, which hinted the specificity of LPIs in HAEC activation; third, LPIs upregulate six types of 640 secretomic genes (SGs), namely, 216 canonical SGs, 60 caspase-1-gasdermin D (GSDMD) SGs, 117 caspase-4/11-GSDMD SGs, 40 exosome SGs, 179 Human Protein Atlas (HPA)-cytokines, and 28 HPA-chemokines, which make HAECs a large secretory organ for inflammation/immune responses and other functions; fourth, LPIs activate transcriptomic remodeling by upregulating 172 transcription factors (TFs), namely, pro-inflammatory factors NR4A3, FOS, KLF3, and HIF1A; fifth, LPIs upregulate 152 nuclear DNA-encoded mitochondrial (mitoCarta) genes, which alter mitochondrial mechanisms and functions, such as mitochondrial organization, respiration, translation, and transport; sixth, LPIs activate reactive oxygen species (ROS) mechanism by upregulating 18 ROS regulators; finally, utilizing the Cytoscape software, we found that three mechanisms, namely, LPI-upregulated TFs, mitoCarta genes, and ROS regulators, are integrated to promote HAEC activation. Our results provide novel insights into aortic EC activation, formulate an EC biology knowledge-based transcriptomic profile strategy, and identify new targets for the development of therapeutics for cardiovascular diseases, inflammatory conditions, immune diseases, organ transplantation, aging, and cancers.

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Section: Resultsmentioning

confidence: 99%

Section: Gpr55 a Specific Receptor For Lpis Is Expressed On The Endothelium Of Both Human And Mouse Aortas And Is Significantly Upregulatmentioning

confidence: 99%

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Xu¹,

Shao²,

Saaoud³

et al. 2021

Front. Cardiovasc. Med.

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“… 58 Moreover, CD27-deficiency caused reduction in Treg cell numbers. 59 , 60 Interestingly, Zhao et al reported CD27 as one of the downregulated transcripts solely differentially expressed in the monocytes of rapidly progressive ALS patients. 61 …”

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2

Giovannelli

Bayatti

Brown

et al. 2021

Brain Communications

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Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with ALS. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis (IMODALS) was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for five days every twenty-eight days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-Treg-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient Treg-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.

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“…CD27-CD70 is a another possible co-inhibitory pair since CD27 paucity on mice models show markedly increased atherosclerotic burden. In addition, CD27 is demonstrated to be essential in maintain a healthy pool of regulatory T cells (Tregs), preventing increased apoptosis of Tregs ( 84 ). CD70 promotes macrophage function and viability, and is important for effective efferocytosis and extrusion of oxLDL.…”

Section: Mechanisms For Macrophage Activationmentioning

confidence: 99%

Dynamic Macrophages: Understanding Mechanisms of Activation as Guide to Therapy for Atherosclerotic Vascular Disease

Decano

Aikawa

2018

Front. Cardiovasc. Med.

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An emerging theory is that macrophages are heterogenous; an attribute that allows them to change behavior and execute specific functions in disease processes. This review aims to describe the current understanding on factors that govern their phenotypic changes, and provide insights for intervention beyond managing classical risk factors. Evidence suggests that metabolic reprogramming of macrophages triggers either a pro-inflammatory, anti-inflammatory or pro-resolving behavior. Dynamic changes in bioenergetics, metabolome or influence from bioactive lipids may promote resolution or aggravation of inflammation. Direct cell-to-cell interactions with other immune cells can also influence macrophage activation. Both paracrine signaling and intercellular molecular interactions either co-stimulate or co-inhibit activation of macrophages as well as their paired immune cell collaborator. More pathways of activation can even be uncovered by inspecting macrophages in the single cell level, since differential expression in key gene regulators can be screened in higher resolution compared to conventional averaged gene expression readouts. All these emerging macrophage activation mechanisms may be further explored and consolidated by using approaches in network biology. Integrating these insights can unravel novel and safer drug targets through better understanding of the pro-inflammatory activation circuitry.

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CD27 co-stimulation increases the abundance of regulatory T cells and reduces atherosclerosis in hyperlipidaemic mice

Abstract: We demonstrate that CD27 co-stimulation increases the number of Tregs and limits lesion development and inflammation in experimental atherosclerosis, particularly during early stages of disease. Thus, our study suggests that promotion of CD27 function may mitigate atherosclerosis.

Cited by 43 publications

References 45 publications

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Novel Knowledge-Based Transcriptomic Profiling of Lipid Lysophosphatidylinositol-Induced Endothelial Cell Activation

Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2

Dynamic Macrophages: Understanding Mechanisms of Activation as Guide to Therapy for Atherosclerotic Vascular Disease

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