T cell subsets and functions in atherosclerosis

Saigusa, Ryosuke; Winkels, Holger; Ley, Klaus

doi:10.1038/s41569-020-0352-5

Cited by 487 publications

(476 citation statements)

References 247 publications

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“…Adaptive immunity has a major role in atherosclerosis ( 1 ), the underlying cause of coronary artery disease (CAD), associated with a variety of antigens that have been described ( 2 ). However, other potential self-antigens remain unknown ( 3 ). It has been proposed that in the chronic inflammatory state present in atherosclerosis, tolerance to self-antigens could be broken through several potential mechanisms, implicating an autoimmune component in atherosclerosis ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

et al. 2020

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The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS). Furthermore, the role of T cells reactive to LL-37 in atherosclerosis was assessed using apoE−/− mice immunized with the LL-37 mouse ortholog, mCRAMP. Peripheral blood mononuclear cells (PBMCs) from patients with ACS were stimulated with LL-37. PBMCs from stable coronary artery disease (CAD) patients or self-reported subjects served as controls. T cell memory responses were analyzed with flow cytometry. Stimulation of PBMCs with LL-37 reduced CD8+ effector T cell responses in controls and patients with stable CAD but not in ACS and was associated with reduced programmed cell death protein 1 (PDCD1) mRNA expression. For the mouse studies, donor apoE−/− mice were immunized with mCRAMP or adjuvant as controls, then T cells were isolated and adoptively transferred into recipient apoE−/− mice fed a Western diet. Recipient mice were euthanized after 5 weeks. Whole aortas and hearts were collected for analysis of atherosclerotic plaques. Spleens were collected for flow cytometric and mRNA expression analysis. Adoptive transfer experiments in apoE−/− mice showed a 28% reduction in aortic plaque area in mCRAMP T cell recipient mice (P < 0.05). Fifty six percent of adjuvant T cell recipient mice showed calcification in atherosclerotic plaques, compared to none in the mCRAMP T cell recipient mice (Fisher’s exact test P = 0.003). Recipients of T cells from mice immunized with mCRAMP had increased IL-10 and IFN- γ expression in CD8+ T cells compared to controls. In conclusion, the persistence of CD8+ effector T cell response in PBMCs from patients with ACS stimulated with LL-37 suggests that LL-37-reactive T cells may be involved in the acute event. Furthermore, studies in apoE−/− mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification.

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Section: Introductionmentioning

confidence: 99%

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

et al. 2020

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“…Naïve CD4 + T lymphocytes can differentiate into different Th effector subpopulations, containing the effector subtypes Th1, Th2, Th9, Th17, and Th22; follicular Th; and the regulatory T lymphocytes (Treg cells) [ 36 ]. Each cell subtype is characterized by specific cytokine profiles and participates in different physiological and pathological responses, but there is a great plasticity among them not fully understood yet [ 37 , 38 , 39 , 40 ]. The specific Th cell differentiation is driven by the exact combination of cytokines and activation of specific transcription factors [ 29 , 41 , 42 , 43 ].…”

Section: Il-17a: a Key Proinflammatory Cytokine And Therapeutic Tamentioning

confidence: 99%

IL-17A as a Potential Therapeutic Target for Patients on Peritoneal Dialysis

et al. 2020

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Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, γδ T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications.

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“…Cardiovascular diseases (CVDs), including coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF), are the leading cause of death in humans and are manly caused by atherosclerosis. Atherosclerosis, characterized by the formation of fat-laden plaques in large-and medium-sized vessels, has been identified as a chronic inflammatory disease of the artery wall (Saigusa et al 2020). Atherosclerosis occurs through the recruitment of monocytes and their differentiation into macrophages, which require lipids for foam cell generation, a process regulated by balancing the rates of lipid uptake and efflux (Peng et al 2020).…”

Section: Introductionmentioning

confidence: 99%

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

Shen

Zhang

Zhu

et al. 2020

Mol Med

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Atherosclerosis, characterized by the formation of fat-laden plaques, is a chronic inflammatory disease. ABCA1 promotes cholesterol efflux, reduces cellular cholesterol accumulation, and regulates anti-inflammatory activities in an apoA-I- or ANXA1-dependent manner. The latter activity occurs by mediating the efflux of ANXA1, which plays a critical role in anti-inflammatory effects, cholesterol transport, exosome and microparticle secretion, and apoptotic cell clearance. ApoA-I increases ANXA1 expression via the ERK, p38MAPK, AKT, and PKC pathways. ApoA-I regulates the signaling pathways by binding to ABCA1, suggesting that apoA-I increases ANXA1 expression by binding to ABCA1. Furthermore, ANXA1 may increase ABCA1 expression. ANXA1 increases PPARγ expression by modulating STAT6 phosphorylation. PPARγ also increases ANXA1 expression by binding to the promoter of ANXA1. Therefore, ABCA1, PPARγ, and ANXA1 may form a feedback loop and regulate each other. Interestingly, the ANXA1 needs to be externalized to the cell membrane or secreted into the extracellular fluids to exert its anti-inflammatory properties. ABCA1 transports ANXA1 from the cytoplasm to the cell membrane by regulating lipidization and serine phosphorylation, thereby mediating ANXA1 efflux, likely by promoting microparticle and exosome release. The direct role of ABCA1 expression and ANXA1 release in atherosclerosis has been unclear. In this review, we focus on the role of ANXA1 in atheroprogression and its novel interaction with ABCA1, which may be useful for providing basic knowledge for the development of novel therapeutic targets for atherosclerosis and cardiovascular disease.

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T cell subsets and functions in atherosclerosis

Cited by 487 publications

References 247 publications

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification

IL-17A as a Potential Therapeutic Target for Patients on Peritoneal Dialysis

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

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