ATVB Distinguished Scientist Award

Ley, Klaus; Gerdes, Norbert; Winkels, Holger

doi:10.1161/atvbaha.117.308611

Cited by 32 publications

(12 citation statements)

References 218 publications

(224 reference statements)

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“…Costimulatory molecules such as Cd86 and Cd40 relevant to antigen presentation were also represented among both in vivo M1(=LPS+)C57BL/6J and in vitro classically activated (LPS+IFN-γ) Mφ signatures (29–31). CD86 is a ligand for CD28 and is a known inflammatory Mφ/DC marker (32).…”

Section: Analysis Criteria Of In Vivo and In Vitro Signatures And Ovementioning

confidence: 99%

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

et al. 2019

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Macrophages are found in tissues, body cavities, and mucosal surfaces. Most tissue macrophages are seeded in the early embryo before definitive hematopoiesis is established. Others are derived from blood monocytes. The macrophage lineage diversification and plasticity are key aspects of their functionality. Macrophages can also be generated from monocytes in vitro and undergo classical (LPS+IFN-γ) or alternative (IL-4) activation. In vivo , macrophages with different polarization and different activation markers coexist in tissues. Certain mouse strains preferentially promote T-helper-1 (Th1) responses and others Th2 responses. Their macrophages preferentially induce iNOS or arginase and have been called M1 and M2, respectively. In many publications, M1 and classically activated and M2 and alternatively activated are used interchangeably. We tested whether this is justified by comparing the gene lists positively [M1(=LPS+)] or negatively [M2(=LPS–)] correlated with the ratio of IL-12 and arginase 1 in transcriptomes of LPS-treated peritoneal macrophages with in vitro classically (LPS, IFN-γ) vs. alternatively activated (IL-4) bone marrow derived macrophages, both from published datasets. Although there is some overlap between in vivo M1(=LPS+) and in vitro classically activated (LPS+IFN-γ) and in vivo M2(=LPS–) and in vitro alternatively activated macrophages, many more genes are regulated in opposite or unrelated ways. Thus, M1(=LPS+) macrophages are not equivalent to classically activated, and M2(=LPS–) macrophages are not equivalent to alternatively activated macrophages. This fundamental discrepancy explains why most surface markers identified on in vitro generated macrophages do not translate to the in vivo situation. Valid in vivo M1/M2 surface markers remain to be discovered.

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Section: Analysis Criteria Of In Vivo and In Vitro Signatures And Ovementioning

confidence: 99%

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

et al. 2019

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“…T-cell costimulatory or coinhibitory pathways are known to play critical roles in enhancing or inhibiting activation of T cells, respectively. The important costimulatory pathway involving the interactions of B7 ligands CD80 and CD86 on DCs with CD28 on T cells has been suggested to play a dominant role in the modulation of T cell functions and atherosclerosis 7 . A recent study showed that normocholesterolemic CD80 −/− /CD86 −/− or CD28 −/− mice exhibited a marked decrease in Tregs and increased incidence and mortality of angiotensin II-induced AAA 11 .…”

Section: Discussionmentioning

confidence: 99%

“…The T-cell costimulatory and coinhibitory pathways are crucial in modulating functions of Teffs and Tregs and their balance. Recent experimental studies using genetically modified mice or blocking antibodies have revealed that the costimulatory and coinhibitory pathways are critically involved in the pathogenesis of atherosclerosis 7 . Interactions of CD28 on T cells with B7 ligands CD80 and CD86 on antigen-presenting cells are the most important costimulatory pathway for T cell activation 8 .…”

Section: Introductionmentioning

confidence: 99%

CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice

Amin

Sasaki

Yamashita

et al. 2019

Sci Rep

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Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E–deficient ( Apoe −/− ) mice or control Apoe −/− mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4 + T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c + dendritic cells in lymphoid tissues. CTLA-4-Tg/ Apoe −/− mice had reduced accumulation of macrophages and CD4 + T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.

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“…When T cells are activated, not only is the T cell receptor engaged, but also costimulatory or coinhibitory molecules modulate the response 36,37 . Most studies involving genetic deletion or inhibition of the interaction between the molecular pairs in murine atherogenic models have shown that the costimulatory molecules OX40-OX40L, CD137-CD137L, CD28-CD80/CD86 and CD40-CD40L are proatherogenic and the coinhibitory molecules CTLA4-CD80/CD86, CD27-CD70, and PD-1-PDL1/2 are atheroprotective.…”

Section: T Cell Costimulatory/coinhibitory Moleculesmentioning

confidence: 99%

T Cells in Atherosclerosis in Ldlr-/- and Apoe-/- Mice

Getz

Reardon

2018

J Immunological Sci

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Atherosclerosis is the underlying basis for most cardiovascular diseases. It is a chronic inflammation affecting the arterial intima and is promoted by hypercholesterolemia. Cells of both the innate and adaptive immune systems contribute to this inflammation with macrophages and T cells being the most abundant immune cells in the atherosclerotic plaques. In this review, we discuss the studies that examined the role of T cells and T cell subsets in Apoe−/− and Ldlr−/− murine models of atherosclerosis. While there is a general consensus that Th1 cells are pro-atherogenic and regulatory T cells are atheroprotective, the role of other subsets is more ambiguous. In addition, the results in the two models of atherosclerosis do not always yield similar results. Additional studies in the two murine models using cell specific gene manipulations are needed.

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ATVB Distinguished Scientist Award

Cited by 32 publications

References 218 publications

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages

CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice

T Cells in Atherosclerosis in Ldlr-/- and Apoe-/- Mice

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