The mammalian gastrointestinal tract contains the largest number of immune cells and harbors a large and diverse population of commensal bacteria that exist in a symbiotic relationship with the host. The gut-resident immune cells are separated from our microbial residents by a single layer of intestinal epithelial cells (IEC). The dynamic cross-talk between IEC, the intestinal microbiota, and local immune cells represents a cornerstone of intestinal homeostasis. The balance between the various immune cell populations and tonic cytokine signals play an important role in determining thresholds of tolerance and immunity in the intestine.
Diet is an important factor for a healthy life. For the most part of human history, the next meal was not a given. Hence, there was a strong selection pressure for adaptation to periods of no or low food consumption during our evolution. Consequently, today’s excessive calorie intake, as it is typical for diets in the western world, results in increasing occurrence of systemic inflammation and widespread diseases. In contrast, calorie restriction has been shown to improve numerous chronic diseases and to prolong the healthy lifespan. In my group, we are re-thinking health in the context of evolutionary adaptation to low food energy intake. Specifically, we focus on the identification of cellular and molecular mechanisms how reduced calorie intake maintains health, prevents and improves inflammatory diseases, and prolongs healthy life.
Our group “Signal Transduction in Health and Disease” (Department of Gastroenterology and Hepatology, Charité Virchow) aims to understand the molecular mechanisms involved in tissue homeostasis, inflammation, and resolution of inflammation. Our main focus is on the transcription factor NF-κB and its role in the intestinal epithelium. Recent studies showed that crosstalk between epithelium and immune cells changes in health and disease, and that is in part due to altered functions of NF-κB. Our group aims to decipher that crosstalk and identify the changes. Our research is highly interdisciplinary and spans different fields including biochemistry, immunology, stem cell biology, and cancer biology.
Maintenance or restoration of vascular homeostasis are critical determinants of health throughout life. Of late, the primary cilium has been identified as a key regulator of vascular homeostasis and regeneration. While impairment of primary ciliary structure and signaling can promote vascular disease and vascular remodeling, strategies aiming to preserve or restore ciliary function emerge as novel therapeutic approaches to maintain vascular health.
Mucociliary clearance is the primary innate defense mechanism of the lung and crucial to maintain lung homeostasis and health. Mucociliary clearance relies on motile cilia on the surface of epithelial cells and a protective mucus gel layer entrapping particles and pathogens to be cleared from the lungs. Recent evidence suggests that the secreted mucin MUC5B that is crucial for the formation of the mucus gel and proper mucociliary clearance is also implicated in the pathogenesis of interstitial lung disease (ILD). ILD can affect children and adults and is characterized by interstitial inflammation, rapid progression of pulmonary fibrosis and subsequent disruption of the alveolar gas exchange ultimately leading to respiratory failure. The understanding of the pathogenesis remains limited and ILD is usually diagnosed in advanced stages when irreversible lung damage has already occurred. Further, only limited therapeutic options are available, which so far, cannot prevent progression of pulmonary fibrosis. By conditional deletion of Nedd4-2 (Nedd4-2-/-) in lung epithelial cells of mice, we recently generated the first mouse model that develops spontaneous pulmonary fibrosis sharing key features with ILD patients allowing us to study lung homeostasis at baseline and early dysregulation leading to the development of interstitial lung disease.
The innate immune system matures early on along with tissue development. In particular, innate lymphoid cells (ILCs, including Natural Killer (NK) cells, already colonize tissues during fetal life and acquire their effector functions already pre-natally. However, exposure to different environmental signals, including microbial infection, can still remodel ILCs and leave permanent epigenetic marks. Our group focuses on delineating transcriptionally and epigenetically the immune functional programs pre-wired during development as well as those emerged and imprinted after exposure to environmental stimuli, in particular persistent virus, thereby setting the threshold of our immune fitness and tolerance to tissue damage. Our aim is to understand the key homeostatic checkpoints, which, once altered, can initiate inflammatory circuits and lead to disease.
Environmental factors such as nutrition but also pollution can significantly influence the health-to-disease transition. The contact of the environment with the human organism, especially at interfaces such as the intestine and the immune system, is of crucial importance. Often, several harmful environmental influences come together to trigger a disease or promote its development. Through our project, we aim to create a better understanding of environmental factors that promote the development of cardiovascular diseases via immunological mechanisms.
Our lab is interested in analyzing immune cells in the tissue context, using state-of-the art, functional intravital microscopy and histocytometry approaches. In addition to reacting to stimuli from hematopoietic and non-hematopoietic cells, for example via direct cell-cell contacts or via soluble mediators, immune cells are exposed to a variety of other stimuli present in the tissue, among them mechanical cues. The significance of those stimuli for immune cells has not been explored in detail. Recently, a role for the mechanosensor Piezo1 in shaping myeloid cell activation has been identified. Here, we aim to understand how mechanical cues in barrier tissues affect the function of myeloid cells. We will focus the lamina propria of the intestine, a tissue that in the healthy organism is constantly subjected to contractions (peristalsis). We hypothesize that this mechanical stimulation impacts on the phenotype of macrophages in the lamina propria. As alterations in peristalsis appear in certain situations, such as parasitic infections, we aim to test to what extent mechanosensing in macrophages affects their function under those conditions.
Our laboratory focuses on the immunological and molecular pathomechanisms of the skin with the aim to identify approaches for personalized and preventive medicine. One group of our translational research interests are chronic inflammatory autoimmune diseases of the skin.
We study development and function of the innate immune system, in particular of innate lymphoid cells (ILC). A current focus is to obtain a molecular understanding of how the innate immune system, by integrating environmental signals, contributes to tissue physiology and health. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are likely to reveal unsuspected pathways by which the immune system might be plumbed to improve health and health span.
Our laboratory investigates the interaction of dietary factors with the gut microbiota and the host, especially with the host’s immune system, in the context of cardiovascular and renal disease. Arterial hypertension and chronic kidney disease (CKD) are of particular interest, as both conditions are associated with a significantly increased cardiovascular risk.
Our research aims to understand the role of tissue-resident cells of the innate immune system in the prevention of chronic inflammatory diseases such as systemic lupus erythematosus and inflammatory bowel disease. Our goal is to identify mechanisms that may inhibit the transition from homeostasis to chronic inflammatory disease and to determine the role of tissue-resident cells of the innate immune system in this process.
Our lab studies the role of immune cells and inflammatory processes in the liver. Infiltration and activation of immune cells play an important role during the development of acute and chronic liver diseases, but the exact molecular and cellular mechanisms leading to the development of liver inflammation have not been fully elucidated until now. We are exploring the inflammatory processes during acute liver failure, non-alcoholic fatty liver disease and steatohepatitis (NASH), liver cirrhosis and liver cancer in order to develop new diagnostic and therapeutic strategies. Furthermore, a better understanding of how both pro- and anti-inflammatory pathways can disrupt the homeostatic processes of a healthy liver is critical for the prevention of liver diseases in the first place.
Resilience to infections is equally defined by the host’s ability to clear the infecting pathogen and to resolve and mitigate secondary injury, and thus to restore and maintain tissue homeostasis. These physiological processes of resolution and repair, however, intersect with pathogenic responses in chronic organ fibrosis.
Biomarkers play a central role in detecting chronic inflammatory diseases before irreversible tissue damage occurs. These measurable, ideally disease-specific, indicators can be detected in the organism even before the onset of symptoms. For example, neutrophil elastase (NE), a serine protease secreted by activated neutrophils and essential for the innate immune response to pathogen infections, already serves as a biomarker for certain chronic inflammatory diseases of the respiratory and digestive tracts
Our laboratory focuses on the mechanisms involved in maintaining oxalate homeostasis. Oxalate is a component of various foods, found in different vegetables, nuts, but also in tea and coffee. High urinary oxalate concentrations lead to kidney stones, the second most common kidney disease after hypertension. Oxalate represents the most common component of kidney stones.