The role of tissue-resident macrophages in invasive candidiasis

We are interested in understanding the role of the macrophages that reside within the kidney, termed kidney-resident macrophages (krMΦs). Although krMΦs are fundamental for kidney homeostasis, it is unclear how they support normal renal function and renal homeostasis. We seek to unravel the underlying mechanisms of how krMΦs mediate kidney resilience at steady state and in inflammation.

The influence of lipidome alterations on dendritic cell functionality in fatty liver (MASLD)

Our lab studies the role of immune cells and inflammatory processes in the liver. During homeostasis the liver plays an important role in adaptation to environmental influences as it is constantly exposed to antigens from the gastrointestinal system, and plays a critical role in maintaining a balance between tolerance to harmless antigens (eg. food proteins or commensal bacteria) and control of pathogens.1 When this balance is disrupted (termed maladaptation) the resulting immune-mediated changes can lead to chronic liver diseases and ultimately cancer.2 Infiltration and activation of immune cells play an important role during the development of 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, metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH), 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.

Mechanisms by which innate immune crosstalk maintains kidney homeostasis and protects from autoimmune organ damage

Tissue resident immune cells maintain organ health by mechanisms that are not well understood. We propose to explore the mechanisms by which ILC crosstalk with resident macrophages to maintain homeostasis in the kidney.

The role of the aryl hydrocarbon receptor and intestinal barrier function in inflammation in CKD

Chronic kidney dysfunction is a major global health concern of increasing prevalence, driving a plethora of secondary comorbidities. A mechanistic understanding of the driving factors is essential to develop preventive and therapeutic concepts. Our research group investigates microbiome-mediated mechanisms of cardiovascular risk (Wilck et al. Nature 2017; Bartolomaeus et al. Circulation 2019; Avery et al. Cardiovasc Res. 2023). CKD is an understudied risk factor for cardiovascular disease. In the long term, microbiome-targeting interventions could help to reduce cardiovascular risk in CKD patients.

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Crosstalk between intestinal macrophages and innate lymphoid cells

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. Understanding such mechanisms may allow to answer the question of why some patients are susceptible to chronic autoimmune-related inflammatory diseases and others are not, and how to improve/achieve resistance to chronic inflammatory diseases.

Effect of the short-chain fatty acid propionate on regulatory T cells in health and chronic kidney disease

In our project, we focus on maladaptive immune responses to prevent multi-morbidity in patients with chronic kidney disease (CKD). Based on our longstanding interest in microbiome-immune interactions in cardiovascular and renal diseases, the planned project involves first proof-of-concept clinical studies side by side with experimental in vitro assays. Our translational project addresses a molecular mechanism that is crucial to maintain health and opens up areas for preventative strategies in line with the Re-thinking health program.

Establishment of human colon assembloids with an immune cell compartment

The gastrointestinal epithelium is organized into clonal crypts that represent sophisticated anatomical and functional tissue units. The epithelium is intimately associated with the mesenchymal stroma network, and various mesenchymal cell types are essential constituents of the stem cell niche that regulates epithelial homeostasis. The gastrointestinal stem cells give rise to differentiated cells. This process is important to maintain the nutritive absorptive functions of the epithelium as well as to build a barrier against pathogens and toxins from the environment. Recently, it has become increasingly evident that interactions between the epithelium and stroma are vital in regulating the barrier function, allowing tissue adaptations to environmental perturbations1,2. Our research aims at understanding the interplay between the epithelium, stroma and the microbiota. We would like to understand how tissues respond to microbiota alterations or exposure to pathogenic bacteria as well as their toxins. To address this, we are also developing new organoid and assembloid models to recapitulate the cellular networks observed in vivo.

Identification of novel strategies to prevent pneumonia in diabetic individuals

Diabetics have a higher risk of various infectious diseases including pneumonia. Current estimates suggest that 450 million people worldwide have diabetes, and this number will increase to approximately 700 million by 2045. The increase in diabetes prevalence is thus likely to cause an increase in pneumonia-related morbidity and mortality. A better understanding of the mechanisms underlying diabetes-related dysregulation of the antibacterial immune response may allow to develop more targeted prophylactic strategies to prevent pneumonia in diabetic individuals.

Role of SLC26A9 chloride transporter in mucociliary clearance in health and chronic inflammatory airways diseases

The airway mucosa represents the first line of defense of the respiratory system against pathogens, pollutants, and irritants that are constantly inhaled during tidal breathing. Elimination of these potentially harmful stimuli by mucociliary clearance is an important innate defense mechanism of the lung, which operates through the coordinated function of (i) the motile cilia, (ii) the airway surface liquid layer, and (iii) the mucus layer.

Maintaining vascular integrity in ARDS with organ-on-chip technology

Acute respiratory distress syndrome (ARDS) is a serious complication of infectious or sterile lung inflammation, typically as a consequence of pneumonia or sepsis, with high morbidity and mortality (30%-40%) and presently no pharmacological or mechanistic treatment strategies. This critical knowledge and treatment gap became strikingly evident in the recent COVID-19 pandemic, with ARDS as the main cause of death1,2. ARDS is characterized by a breakdown of the lung vascular barrier and the leak of fluid from the blood into the airspaces, preventing normal lung mechanics and gas exchange. Traditionally, mechanisms of ARDS are studied in animal models, which have, however, translated poorly into the clinical scenario. Here, we will assess mechanisms of lung vascular barrier integrity and regeneration in a novel microphysiological Microvasculature-on-Chip (MOC) model that allows to track vascular morphology and leak as well as the dynamics of individual cell types and their interaction in an unprecedented temporal and spatial context. Here, we will employ this model for the first time to study lung vascular barrier integrity, and to devise strategies for its maintenance in experimental settings mimicking ARDS.

Role of the sulfate transporter SLC26A1 in musculoskeletal health

Sulfate is an ion that is indispensable for human health. It is necessary for the formation of connective tissues, including bone and cartilage. The kidney plays a central role in body ion homeostasis by reabsorbing electrolytes from the tubular fluid. Specifically, the proximal tubule is a major site for fluid, protein, and nutrient retrieval. Our working groups recently described a patient who presented with unexplained chronic chest pain and a kidney stone.

No cyst is alike – studying a distinct PKD2-founder variant for better explaining disease variability

Our group is interested in identification and investigation of genetic, clinical, and environmental factors determining onset of chronic kidney disease (CKD) and kidney survival. We make use of next-generation sequencing techniques and deep-phenotyping to identify genetic variants that are predictive for disease progression or convey protection from organ failure. We functionally evaluate identified germline variants in vitro in order to understand underlying molecular mechanisms leading to CKD on the one hand or protecting from kidney failure on the other. By doing so, we aim at defining and targeting molecular switches responsible for health maintenance and disease alleviation.

Innate lymphoid cells and metabolic homeostasis

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 (such as those derived from nutrients, microbiota, circadian rhythm) contributes to tissue physiology. Recent studies have revealed ever more intriguing relationships between innate immune system components and basic developmental and biologic processes that are

Antibiotic use during pregnancy and increased risk for allergic asthma in the next generation

We are a reproductive immunology group studying pregnancy, allergy and immune system development. The Developmental Origins of Health and Disease hypothesis posits that perinatal environmental exposures, during the fetal and early neonatal life stages, can influence childhood immune system development and alter disease susceptibility later in life. Demonstrating this, epidemiological studies show that the use of antibiotics during pregnancy is associated with an increased risk for allergic asthma in childhood.1 Since antibiotics account for 80% of the medications prescribed during pregnancy, it is increasingly important to understand the connection between prenatal antibiotic exposure and allergic asthma risk. To study this, we recently designed a model in which treatment of pregnant mice with the antibiotic vancomycin resulted in increased severity of allergic asthma in the offspring. We found that antibiotic treatment during pregnancy caused detrimental changes to the maternal gut microbiome, known as microbial dysbiosis, which was then passed on to the offspring.2 In early neonatal life, the gut microbiome interacts very closely with the developing immune system, and we found that the transfer of an antibiotic-altered gut microbiome from mother to offspring programs the immune system to become hyperreactive, which likely increases offspring asthma susceptibility. We would like to further this research by testing possible treatments, such as supplementation with probiotics or immunomodulatory short-chain fatty acids, that can help the maternal gut microbiome recover after exposure to antibiotics during pregnancy.

Role of the oxalate transporter SLC26A6 in maintaining kidney health

Our laboratory focuses on the mechanisms involved in maintaining oxalate homeostasis. Oxalate is a component of various foods and is absorbed via the intestine. High urinary oxalate concentrations lead to kidney stones, the second most common kidney disease after hypertension. Furthermore, we have shown that elevated blood oxalate concentrations are associated with cardiovascular disease. We are working translationally and recently demonstrated that oxalate uptake in the intestine can be reduced via an enzyme isolated from bacteria in patients.