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Helmholtz Munich | Markus Rehberg

Rehberg Lab

Our research aims to elucidate the innate immune response at the alveolar barrier after contact with inhaled environmental agents (i.e. particles, viruses), that initially contribute to the maintenance of physiologic conditions, but may ultimately lead to (chronic) lung disease.

Our research aims to elucidate the innate immune response at the alveolar barrier after contact with inhaled environmental agents (i.e. particles, viruses), that initially contribute to the maintenance of physiologic conditions, but may ultimately lead to (chronic) lung disease.

Immune responses at the alveolar barrier

To investigate the cellular responses, we apply state of the art intravital microscopy on the alveolar region of the murine lung. We want to visualize and determine in real-time elements of the pulmonary immune response under physiologic and pathophysiologic conditions upon inhalation of adverse agents or novel nano-technology based drug carriers. This unique approach enables us to study (sub-)cellular dynamic events, which were inaccessible up to now. Our research will contribute to a deeper understanding of the initiation and chronicity of lung inflammation and to the evaluation of novel therapeutic strategies.

Picture left: Intravital microscopic image of innate immune cells in the alveolar region of the lung. Alveoli and surrounding tissue, containing micro-vessels are highlighted by reflected light (red). Platelets (bright red), neutrophils (green) and alveolar macrophages (blue) are depicted.

Scientists at Rehberg Lab

Chenxi Li

PhD Student

Yasmin Shaalan

PhD Student

Haiyun Zhang

PhD Student


2022, Review in Frontiers in Immunology

Applications and immunological effects of quantum dots on respiratory system.

Quantum dots (QDs), are one kind of nanoscale semiconductor crystals with specific electronic and optical properties, offering near-infrared mission and chemically active surfaces. Increasing interest for QDs exists in developing theranostics platforms for bioapplications such as imaging, drug delivery and therapy. Here we summarized QDs' biomedical applications, toxicity, and immunological effects on the respiratory system. Bioapplications of QDs in lung include biomedical imaging, drug delivery, bio-sensing or diagnosis and therapy. Generically, toxic effects of nanoparticles are related to the generation of oxidative stresses with subsequent DNA damage and decreased lung cells viability in vitro and in vivo because of release of toxic metal ions or the features of QDs like its surface charge. Lastly, pulmonary immunological effects of QDs mainly include proinflammatory cytokines release and recruiting innate leukocytes or adaptive T cells.

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2022, Scientific Article in Nature Communications

The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD.

Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.

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2022, Scientific Article in Cardiovascular Research

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation.

AIMS: Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signaling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signaling. METHODS AND RESULTS: Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store operated Ca2+ entry (SOCE) through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signaling, thereby preventing cellular spreading, adhesion strengthening and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of E.coli particles by neutrophils in the absence of KV1.3. CONCLUSION: We show that the voltage gated potassium channel KV1.3 is critical for Ca2+ signaling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signaling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration. TRANSLATIONAL PERSPECTIVE: Neutrophils exert important immune functions during tissue injury or bacterial infection through leaving the vasculature and extravasate into affected tissues. Conversely, neutrophils trigger the pathogenesis of acute and chronic inflammatory disorders and are involved in the development and maintenance of various autoimmune diseases. Within this study, we show that the voltage-gated potassium channel KV1.3 is functionally expressed on neutrophils and affects calcium signaling thereby regulating neutrophil effector functions during immune responses. Hence, KV1.3 represents an interesting potential new target to treat unwanted excessive neutrophil invasion in various disorders ranging from autoinflammatory disorders to ischemic tissue injury.

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2021, Scientific Article in Frontiers in bioengineering and biotechnology

A bioinspired in vitro lung model to study particokinetics of nano-/microparticles under cyclic stretch and air-liquid interface conditions.

Evolution has endowed the lung with exceptional design providing a large surface area for gas exchange area (ca. 100 m2) in a relatively small tissue volume (ca. 6 L). This is possible due to a complex tissue architecture that has resulted in one of the most challenging organs to be recreated in the lab. The need for realistic and robust in vitro lung models becomes even more evident as causal therapies, especially for chronic respiratory diseases, are lacking. Here, we describe the Cyclic In VItro Cell-stretch (CIVIC) “breathing” lung bioreactor for pulmonary epithelial cells at the air-liquid interface (ALI) experiencing cyclic stretch while monitoring stretch-related parameters (amplitude, frequency, and membrane elastic modulus) under real-time conditions. The previously described biomimetic copolymeric BETA membrane (5 μm thick, bioactive, porous, and elastic) was attempted to be improved for even more biomimetic permeability, elasticity (elastic modulus and stretchability), and bioactivity by changing its chemical composition. This biphasic membrane supports both the initial formation of a tight monolayer of pulmonary epithelial cells (A549 and 16HBE14o−) under submerged conditions and the subsequent cell-stretch experiments at the ALI without preconditioning of the membrane. The newly manufactured versions of the BETA membrane did not improve the characteristics of the previously determined optimum BETA membrane (9.35% PCL and 6.34% gelatin [w/v solvent]). Hence, the optimum BETA membrane was used to investigate quantitatively the role of physiologic cyclic mechanical stretch (10% linear stretch; 0.33 Hz: light exercise conditions) on size-dependent cellular uptake and transepithelial transport of nanoparticles (100 nm) and microparticles (1,000 nm) for alveolar epithelial cells (A549) under ALI conditions. Our results show that physiologic stretch enhances cellular uptake of 100 nm nanoparticles across the epithelial cell barrier, but the barrier becomes permeable for both nano- and micron-sized particles (100 and 1,000 nm). This suggests that currently used static in vitro assays may underestimate cellular uptake and transbarrier transport of nanoparticles in the lung.

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2019, Scientific Article in Nature

FSP1 is a glutathione-independent ferroptosis suppressor.

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids(1,2). To date, ferroptosis has been thought to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)(3,4) and radical-trapping antioxidants(5,6). However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis(7) is crucial to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints(8) and phospholipid composition(9,10) contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene(11), confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q(10), CoQ(10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ(10) using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1-CoQ(10)-NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis.

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Prof. Dr. Markus Rehberg

Head of in vivo imaging