Application 2020

IL-1 family proteins are critical regulators of inflammation. The new IL-1 family receptor antagonist IL-38, which is released from apoptotic cells, promotes the resolution of inflammation partly due to its impact on pathogenic T cells such as γδ T cells. The project explores other mechanisms of the pro-resolving nature of IL-38, including its impact on the generation of auto-antibodies, and investigates the so-far elusive molecular mechanisms of IL-38 signaling. To achieve these goals in vitro models of immune cell activation, in vivo inflammation models, and patient material will be employed.

Necroptosis and apoptosis differentially regulate immune responses. This project aims at elucidating the role of necroptosis versus apoptosis in the resolution of inflammation. The effects of necroptotic/apoptotic cells on the release of regulators of the resolution of inflammation and on the phenotype of cocultivated activated macrophages and DCs will be analyzed. In an in vivo model of zymosan-induced peritonitis, necroptotic/apoptotic fibroblasts will be injected i.p. to examine their effects on the resolution of inflammation.

Acetaminophen (APAP)-induced acute liver injury (ALI) not only is a continual clinical problem but as experimental protocol a well-established paradigmatic model of drug-induced necroinflammation. Recent studies imply that inter-organ communication may affect course and resolution of APAP-induced ALI, though contributing mechanisms remain elusive. In this PhD project we aim to identify crucial biological signals (e.g. TLR ligands, (bacterial) metabolites, cytokines, hormones) that are derived from non-hepatic sources (e.g. intestine, lung, spleen, adrenal glands) during the acute phase of APAP-induced ALI and potentially feedback on the resolution phase of the intoxication.

Biosynthesis of pro-resolving lipid mediators such as lipoxins and resolvins is dependent on the interplay of macrophage/granulocyte-derived 5- and 15-lipoxygenases (LO). Efferocytosis of dying neutrophils by 15-LO positive macrophages plays a central role in the resolution of inflammation. This projects aims to investigate the mechanism of SPM biosynthesis in co-incubations of human monocyte-derived macrophages with dying neutrophils. For this, monocytes will be isolated from human leukocyte concentrates, in vitro differentiated and co-incubated with neutrophils. Subsequently, expression and interplay of lipoxygenases and other enzymes involved in SPM biosynthesis as well as SPM formation will be investigated.

The expression/activity of the soluble epoxide hydrolase (sEH) is important for optimal progenitor cell proliferation and long-term sEH inhibition is detrimental to progenitor cell proliferation, mobilization and vascular repair. We hypothesize that the sEH plays an important role in the regulation of myeloid cell function and aim to determine the role of the sEH in regulating macrophage polarization, lipid storage and foam cell development in the frame of atherosclerosis. Use will be made of available proteomic and metabolomic approaches, pharmacological tools as well as siRNA/CRISPR approaches and genetic mouse models e.g. the myeloid-specific deletion of the sEH.

Gene expression changes during the course of inflammation and its resolution are rather well established. There is ample evidence that especially during the resolution phase RNA expression changes are strongly controlled on a post-trancriptional level. In the present project, we aim to elucidate the translational changes in macrophages during the resolution of inflammation and characterize the functional impact of translational changes on the course of the resolution phase.

Mast cells are known for their proinflammatory properties i.e. in promoting allergies. However, they have also the power to suppress immune answers and to promote resolution of inflammation. Here, we aim to identify signals that induce the selective release of antiinflammatory and pro-resolving mediators from mast cells as well as the downstream effector cells targeted by these mediators.

In a running PhD project of the graduate school, we investigate the role of IKKe in inflammatory processes of peritonitis and atherosclerosis in mice. Our current results indicate that a deletion of IKKe ameliorates the inflammatory symptoms and leads to an improved health status. Interestingly, by examining immune cells in IKKe knock-out and wild type mice we detected a significantly increased level of specialized T-cells in several tissues of IKKe-depleted mice. In a follow-up project, we now intend to investigate 1. if the effects of IKKε deletion can be mimicked by the specific IKKe inhibitor drug amlexanox and if this drug can enhance the resolution of inflammation, 2. if IKKe deletion in mice slows down the progression of atherosclerosis and 3. if T-cell subsets play a role in IKKe-mediated effects on inflammatory processes.

Chronic inflammatory diseases are characterized by an impaired resolution of inflammation. This project aims to make use of a natural product-derived kinase inhibitor (synthetic carbazole derivative C81) to promote the resolution of inflammation. The pharmacological action of C81 will primarily be investigated in vitro in human leukocytes: In particular, the influence of C81 on cell functions of macrophages and neutrophils as well as on macrophage polarization processes will be analyzed in detail. Moreover, we will focus on the underlying mechanisms of action with a special emphasis on the kinase signaling network involved.

We have identified that some lipid mediators elicit anti-inflammatory responses by the activation of nuclear receptors. Preliminary data suggest that subsequent recruitment of nuclear repressors to segments of the DNA eventually mediate the resolution response. In the project, vascular nuclear repressors will be studied for their function in inflammation resolution in cultured vascular cells and mouse models of the cardiovascular system.

Using a new transgenic model of Reg3b overexpression in the intestine, we could observe a profound effect of Reg3b in wound healing in an acute model of colitis. Current efforts aim to characterize the exact molecular mechanisms that are controlled by Reg3b with a particular focus on changes in the tumor microenvironment. Moreover, we will elucidate the impact of Reg3b on sporadic intestinal tumorigenesis.