Signals derived from dying cells
Cell Death is central during inflammation. Immune cells die after activation by pathogen-derived mediators, while other cells loose viability in response to exogenous (paracetamol and other drugs) or endogenous noxes (Fas/FasL, hypoxia). Different modes of cell death are known, including apoptosis, necrosis, or necroptosis. It is not understood how the resolution of inflammation is differentially influenced by these types of cell death. Cluster 1aims to answer this question and comprises three projects:
Project 1:Interleukin 38 as a new regulator of the resolution of inflammation
IL-1 family proteins are critical regulators of inflammation. The new IL-1 family receptor antagonist IL-38, which is released from apoptotic cells, blocks the generation of TH17 cells. The project follows the hypothesis that IL-38 constitutes a novel endogenous mediator of the resolution of inflammation. This hypothesis will be tested using in vitro models of immune cell activation, in vivo inflammation models that allow interrogating resolution, and patient material.
Project 2:The role of necroptosis versus apoptosis in the resolution of inflammation
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.
Prof. Dr. Simone Fulda
Institute for Experimental Cancer Research in Pediatrics
University Hospital Frankfurt
Project 3:Termination of necroinflammation mediating recovery from Paracetamol-induced liver injury
Depending on the dose, paracetamol-induced hepatic necroinflammation and injury can either be fatal or reversible with organ regeneration prevailing. Herein, mechanisms that determine successful recovery from liver damage will be investigated in experimental para- cetamol-induced hepatic injury. Results obtained may advance current knowledge of paradigmatic paracetamol intoxication and may likewise open the avenue to novel strategies for the treatment of hepatic inflammatory diseases.
Prof. Dr. Heiko Mühl
Institute of General Pharmacology and Toxicology
Polarization of immune cells
Phagocytosis of dying cells, cell debris or pathogens by macrophages and mast cells, is an important process during resolution of inflammation. The projects within cluster 2 deal with polarization of phagocytes induced by endogenous and exogenous signals and explore signal transduction pathways activated or inhibited during phagocyte-induced resolution of inflammation. Cluster 2 comprises five projects:
Project 4:5-/15-Lipoxygenase interaction as regulatory principle in the lipoxin synthesis during resolution of inflammation
The formation of specialized proresolving mediators (SPM) such as lipoxins and resolvins requires the concerted action of 5-lipoxygenase (5-LO) and 12-LO or 15-LO. The regulation of LOs in monocytes and polarized macrophages as well as the biosynthetic pathways involved in SPM formation will be investigated in this project.
Prof. Dr. Dieter Steinhilber
Institute of Pharmaceutical Chemistry
Project 5:Role of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) in macrophage polarization and resolution of inflammation
Cytochrome P450 (CYP) enzymes generate lipid epoxides from endogenous polyunsaturated fatty acids that are further metabolized by the soluble epoxide hydrolase (sEH). This project will determine the importance of CYP2S1, Cyp2c44 and sEH products in macrophage polarization and in the maintenance versus resolution of inflammation. Use will be made of mice lacking CYP and the sEH in myeloid cells and in vivo models will focus on acute peritonitis and atherosclerosis.
Prof. Dr. Ingrid Fleming
Institute for Vascular Signalling
Goethe University Frankfurt
Project 6:mPGES-1 in macrophages during resolution of inflammation
The microsomal prostaglandin E synthase (mPGES-1), together with cyclooxygenase, produces prostaglandin E2 (PGE2). Despite known as a pro-inflammatory agent, PGE2 also adds to macrophage polarization during resolution of inflammation. Molecular mechanisms how PGE2 causes resolution of inflammation remains elusive. Having specific inhibitors available, we block mPGES-1 and follow the behavior of macrophages in vitro and in vivo, determine mRNA profiles (deep-sequencing), and characterize relevant targets by knockdown/knockout vs. overexpression strategies.
Project 7:Regulation of resolution of inflammation by mast cells
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. So far signals that switch mast cells from a proinflammatory to an antiinflammatory phenotype are largely unknown. Here, we aim to identify signals that promote antiinflammatory phenotypes in mast cells as well as downstream effector cells mediating the mast cell-dependent resolution of inflammation.
Prof. Dr. Klaus Scholich
Institute of Clinical Pharmacology
Project 8:The role of IKKε in the resolution of inflammation in atherosclerosis
IκB kinase ε (IKKε) modulates NF-κB signal transduction cascades and inflammatory reactions. In our project, we aim to investigate the role of IKKε in macrophages in the resolution of inflammation, which is disturbed in atherosclerosis. Therefore, we will perform cell culture experiments as well as mouse models of peritonitis and atherosclerosis using wild type, ApoE knockout and ApoE/IKKε double knockout mice with or without IKKε inhibitor, respectively.
Prof. Dr. Ellen Niedernberger
Institute of Clinical Pharmacology
Restoration of barrier function
A key process during inflammation is the loss of epithelial and endothelial barrier function. This enables immune cells to invade the subendothelial space or allows noxious substances to enter the body and trigger immune reactions. Restoration of barrier function is a fundamental principle during the resolution of inflammation. Regeneration of biological barriers requires a crosstalk between cells of the barrier and (anti-inflammatory) immune cells. Underlying signalling pathways are analysed within the three projects of cluster 3:
Project 9:Pharmacological inhibition of BMP2K to promote resolution of inflammation
Chronic inflammatory diseases are characterized by constant leukocyte infiltration and ongoing angiogenesis due to an endothelial barrier dysfunction. This project aims to restore the barrier functionality of the endothelium and to promote the resolution of inflammation. BMP2K, an as yet widely uncharacterized kinase, is primarily addressed by the small molecule inhibitor C81. The application of C81 as well as BMP2K knockdown experiments will be used to achieve a successful resolution of inflammation.
Prof. Dr. Robert Fürst
Institute of Pharmaceutical Biology
Project 10:Role of the NADPH Oxidase Nox4 in the termination of vascular inflammatory reaction after vascular injury
Nox4 is a hydrogen peroxide producing NADPH oxidase. It is upregulated after vascular injury and its loss results in inflammatory activation, vascular dysfunction and accelerated atherosclerosis. Using mouse models and patient samples, the role of Nox4 in restenosis and resolution of inflammation after injury will be determined. Redox-proteomics will be used to identify Nox4-differentially oxidized proteins. These will be subsequently tested to alter the course of inflammation after vascular injury.
Prof. Dr. Ralf P. Brandes
Institute of Cardiovascular Physiology
Goethe University Frankfurt
Project 11:Functional analysis of Reg3β in the wound healing of acute colitis
The regenerating (Reg) protein family was discovered independently during acute pancreatitis and pancreatic islet regeneration. The Reg3 subclass family member, Reg3β is up-regulated upon tissue damage or after microbial invasion. Stat3 knockout mice show impaired wound healing during acute colitis. Reg3β is a Stat3 downstream target gene in murine intestinal epithelial cells. It is not known whether the worsened healing of Stat3 knockout mice is due to diminished Reg3β expression.
Prof. Dr. Florian Greten