Esther Lutgens (Netherlands)

Amsterdam UMC - location AMC Medical Biochemistry
Esther Lutgens, MD, PhD (1975), is Professor of Experimental Vascular Immunopathology at the AmsterdamUMC. Her research merges basic immunology with vascular biology and metabolism. In her multidisciplinary team, Lutgens combines immunological techniques with cell biology, state-of-the-art animal models for atherosclerosis and metabolic disease, development of small molecule inhibitors, and human pathology. Her work identified the importance of the immune checkpoint protein CD40L and its receptor CD40 in cardiovascular disease. Specifically, Lutgens discovered that inhibiting the co-stimulatory immune checkpoint CD40L-CD40 dyad, a key player in modulating immune responses, results in atherosclerosis regression, thereby reducing the chance of cardiovascular conditions such as myocardial infarction and stroke. More recently, Lutgens has foused on immune checkpoints in atherosclerosis and metabolic syndrome. In one of many groundbreaking projects, she discovered that platelet CD40(L) and leukocyte CD40 cruciallydrive atherosclerosis by regulating major immunologicpathways. Based on her immune checkpoint research, Lutgens untangled the role of TNF-receptor associatedfactors (TRAFs) in CD40-signaling routes in atherosclerosis.She revealed that the CD40-TRAF6 pathway is vital to atherosclerosis, whereas the CD40-TRAF2 pathway is keyto maintaining immunological functions such as T cellactivation and antibody production. Building on this work, Lutgens established a library of innovative small molecule inhibitors (SMIs) that block CD40-TRAF6 interactions. These SMIs potently curb the progression of several chronic inflammatory diseases, including atherosclerosis, multiple sclerosis, and type 2 diabetes. Lutgens' SMIs are just steps away from clinical application and should safely regulate an important immunological pathway, thereby mproving treatment of atherosclerosis and metabolic syndrome. Notably, Lutgens successfully collaborated with a team led by Willem Mulder to deploy these SMIs as a nano-immunotherapy, which is highly effective in mice and safe in nonhuman primates. In 2018, shefounded Cartesio Therapeutics to accelerate SMIs' clinical development. The SMI platform will be further optimized using medicinal chemistry and tested in larger animal models of atherosclerosis and type 2 diabetes. Lutgens has also obtained further insights into precise cell-type-specific actions of CD40-CD40L and their signal transduction pathways in atherosclerosis. With her team, she has identified mechanisms for other immune checkpoints, including GITR, CD27, CD70, and CBL-b, involved in atherosclerosis. She is currently working with immune cells obtained from patient cohorts suffering from cardiovascular disease and type 2 diabetes. By using (single cell) RNA sequencing as well as mass-cytometry approaches, Lutgens aims to clarify the immune checkpoint landscape and interactome during both health and (cardiovascular) disease. This new knowledge of immune checkpoints brings translation from the lab to the clinic ever closer.

Author Of 3 Presentations

The Interface of Immune and Metabolic Responses in Atherosclerosis (ID 1322)

Session Type
Plenary Session
Session Time
09:30 - 11:03
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
10:13 - 10:33

O025 - The Polycomb Repressive Complex 2 (PRC2) in macrophages and atherosclerosis (ID 649)

Session Type
Vascular Biology
Session Time
16:00 - 17:30
Date
Mon, 31.05.2021
Room
Hall E
Lecture Time
16:46 - 16:54

Abstract

Background and Aims

Macrophages are key regulators of inflammatory responses in atherosclerosis. Since epigenetic processes are important in controlling macrophage function, interfering with epigenetic pathways might be a novel approach to combat atherosclerosis. Histone H3K27 trimethylation is a repressive histone mark catalyzed by the Polycomb Repressive Complex 2 (PRC2) with EZH2 as the catalytic subunit. We previously showed that myeloid deletion of Kdm6b, an enzyme that in contrast to PRC2 removes repressive H3K27me3 marks, results in advanced atherosclerosis. Because of its opposing function, we here studied macrophage EZH2 and JARID2, both part of the PRC2 complex, in macrophage activation and atherosclerosis.

Methods

Myeloid-specific Ezh2 (Ezh2del) and Jarid2 (Jarid2del) deficient mice strains were generated (LysM-Cre+ x Ezh2fl/fl or Jarid2fl/fl) and bone marrow from Ezh2del or Ezh2wt mice was transplanted to Ldlr-/- mice which were fed a high fat diet for 9 weeks to study atherosclerosis.

Results

Atherosclerotic lesion size was significantly decreased in Ezh2del transplanted mice compared to control. The percentage of macrophages in the lesions was similar. However neutrophil numbers were lower in Ezh2del transplanted mice. Correspondingly, the migratory capacity of neutrophils was decreased. Moreover, peritoneal Ezh2del foam cells showed a reduction in the inflammatory response with reduced production of IL-6, IL-12 and NO. Currently, we are investigating the effects of JARID2 as important co-factor for the PRC2 complex on macrophage inflammatory responses by use of the Jarid2del mouse strain and siRNA’s against JARID2 in human macrophages.

Conclusions

Myeloid Ezh2 deficiency impairs neutrophil migration and reduces macrophage foam cell inflammatory responses, both contributing to reduced atherosclerosis.

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O026 - Histone methyltransferase DOT1L regulates macrophage inflammatory responses and lipid metabolism (ID 489)

Session Type
Vascular Biology
Session Time
16:00 - 17:30
Date
Mon, 31.05.2021
Room
Hall E
Lecture Time
16:54 - 17:02

Abstract

Background and Aims

DOT1L is the only histone methyltransferase for H3K79 and has recently emerged as a central player in the immune system.

Methods

Here we investigate the role of DOT1L in macrophages by application of a selective DOT1L inhibitor on either mouse or human macrophages and using myeloid-specific Dot1l deleted mice. Furthermore, we investigated myeloid Dot1l in vivo in a mouse model for atherosclerosis including scRNAseq on atherosclerotic plaques.

Results

Using RNA-seq and in vitro assays, we found that Dot1l represses macrophage activation and impacts cellular lipid metabolism. ChIP-seq for H3K79me revealed that DOT1L regulates H3K79 methylation of RXRα in macrophages, leading to reduced RXRα mRNA and protein expression, both upon Dot1l deletion as well as DOT1L inhibition. Given the established role for RXRα in controlling macrophage activation and lipid homeostasis, the phenotype we observe can thus be at least partly explained by impaired RXRα signaling. Moreover, we could induce a similar suppressed lipid phenotype using an RXRα antagonist in wild-type macrophages.

In vivo, we confirmed that myeloid Dot1l deletion increases the activation of plaque macrophages. Moreover, although plaque area was not affected, Dot1l deficiency led to enhanced necrosis, indicating potential plaque destabilization. Apart from these direct effects, we found that myeloid Dot1l also affects other immune cell subsets illustrated by reduced production of IgG and IgM antibodies targeting atherosclerosis-related antigens.

Conclusions

Our data show that myeloid DOT1L is a critical regulator of macrophage inflammatory responses and lipid homeostasis and that it impacts in vivo immune responses and atherosclerosis development.

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Presenter of 1 Presentation

The Interface of Immune and Metabolic Responses in Atherosclerosis (ID 1322)

Session Type
Plenary Session
Session Time
09:30 - 11:03
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
10:13 - 10:33