Immunology and Cell Biology
Main Emphasis
Detailed knowledge on immune signaling and its dysregulation in pulmonary diseases is a prerequisite to identify new therapeutic targets for therapy of chronic lung diseases. Regulation of intracellular protein degradation and membrane signaling in barrier and immune cells are the main research topics in our group.
Immunoproteasome research (Meiners lab)
One research focus is on the immunoproteasome, a specialized type of proteasome in immune cells. It is constitutive for immune cells but inducible in non-immune cells and plays a key role in regulating immune and stress responses. The function of mixed types of proteasomes is not well understood.
Our research aims to elucidate the role of the immunoproteasome for immune cell function and its dysregulation in disease. Currently, we are establishing novel transgenic animal models for immunoproteasome-related research which we aim to use for validation of specific immunoproteasome inhibitors as a new treatment approach for inflammatory and chronic diseases. For clinical studies, we have established medium-throughput proteasome activity profiling in peripheral blood cells to screen large patient or population-based cohorts for altered proteasome activities.
Cell signaling (Orinska lab)
Our focus is the regulation of B cell and mast cell (MC) function and their role in immune response in physiological settings and chronic lung diseases (CLDs). Specifically, we would like to understand how membrane proteins of the tetraspanin family are involved in the regulation of immune cell function and whether/how targeting of tetraspanins would be applicable for treatment of CLD. By using different genetic mouse models and antibody-mediated tetraspanin targeting we are characterizing cell type-specific tetraspanin interaction partners and tetraspanin function.
Leibniz-Gemeinschaft „ImmunoPROteasomes in LUNG health and disease“ – PRO-LUNG
We here explore the concept that the inducible nature of the immunoproteasome enables dynamic adaptation of proteasome function in immune and stress responses. In particular, we aim to understand whether standard, immuno- and the various types of mixed proteasomes have distinct functions e.g. by localizing to distinct cell types or subcellular sites, degrading different substrates, or by interacting with defined proteasome regulators. Solving these questions is key for a detailed understanding of the function of immunoproteasomes in health and disease. It will pave the way for validation of the immunoproteasome as a therapeutic target allowing specific inhibition of single or multiple immunoproteasome subunits in disease with novel site-specific immunoproteasome inhibitors that are currently being developed.
Leibniz Center for Infection: “Sex-specific regulation of immunoproteasome function determines response to infection“
(together with Bianca Schneider, FZB)
In this project, we investigate the (biological) sex-specific regulation of the immunoproteasome and whether this might contribute to the stronger immune responses against infections in females. We are using influenza and tuberculosis-related infection models in female and male mice to dissect the immunoproteasome related immune response as well as in vitro cellular models for sex-hormone treatment. The aim is to unravel the molecular basis of sex-related regulation of the immunoproteasome, which may enable us to develop sex-specific diagnostic tools and target the immunoproteasome therapeutically in a sex-related manner.
Regulation of MrgprB2-mediated mast cell activation by tetraspanin CD37
MC receptor associated with nociception and type 2 inflammation is MrgprB2 (Mas-related G-protein coupled receptor member B2). MrgprB2 is receptor sensing heterocyclic chemical compounds, endo-/exogenous peptides, and neuropeptides involved in the perception of pain and itch. Acting as MrgprB2 ligands chemical compounds and bioactive peptides induce MC activation. This leads to MC degranulation, selective release of different mediators and local or systemic inflammation.
How MrgprB2-mediated MC degranulation is regulated, and whether membrane proteins affect MrgprB2-ligand binding and specificity, is unknown. We identified tetraspanin CD37 as regulator of MrgprB2-mediated MC response. Our initial findings indicate the existence of stimulus-specific regulatory mechanisms of MrgprB2-mediated MC response and characterize CD37 as negative regulator of MrgprB2-mediated MC activation.
Epitope-specific CD37 targeting in mouse as tool to modulate B cell function
CD37 is glycosylated membrane protein highly expressed in B cells. As other tetraspanins CD37 is involved in regulation of incoming receptor-derived signals, lateral membrane protein interactions and intracellular signal processing. Here we are characterizing mouse CD37-specific monoclonal antibodies and investigating the effects of epitope-specific CD37 targeting in vitro and in vivo. Generated CD37-specific monoclonal antibodies recognized two different epitopes in large extracellular loop. Added to the purified B cells in vitro, CD37 Abs induced B cell death, strongly potentiated by Ab crosslinking, Targeting of different CD37-epitopes led to depletion of different B cell subsets in vivo. Despite this, we observed induction of specific immune response to injected antibodies indicating the activation of particular B cell populations. We are going to dissect mechanisms responsible for B cell depletion potentially interesting for treatment of autoimmune diseases and induction of immune response important in development of new vaccine technologies in further experiments.
Third-party funding
- Leibniz Best Minds: Programme for Women Professors: „ImmunoPROteasomes in LUNG health and disease“
(2021-2025) - Leibniz Center for Infection (LCI): “Sex-specific regulation of immunoproteasome function determines response to infection“
(together with Bianca Schneider, FZB, 2023-2025) - DFG/ANR: "The role of the proteasome activator PA200 in myofibroblast differentiation and fibrosis of the lung"
(2021 – 2024) - DFG: “Regulation of the human proteostasis network under mitochondrial protein import stress” within the SPP 2453
(2024 – 2027) - Dorothea-Erxleben award of the excellence cluster “precision medicine in inflammation”
(2024)
- Primary culture of human and mouse lung and immune cells
- Biochemical analyses of proteasome activity (native gel, substrate-based activity tests and activity-based probe analysis)
- Viral infections, lentiviral gene transduction and CrispRCas9-based gene editing
- Molecular biology-based methods
- Cell biological assays for growth, survival, migration and differentiation
- CD8+ T-cell reporter assays
- MC degranulation assays
- Analysis of B cell differentiation, maturation and specific antibody response
- Multiparametric flow cytometry
2024
Meiners, S, Reynaert, NL, Matthaiou, AM, Rajesh, R, Ahmed, E, Guillamat-Prats, R, Heijink, IH & Cuevas-Ocaña, S 2024, 'The importance of translational science within the respiratory field', Breathe, Jg. 20, Nr. 1, S. 230183. https://doi.org/10.1183/20734735.0183-2023
Parvathy, GH, Bhandiwad, D, Eggers, L, Borstel, LV, Behrends, J, Hein, M, Hertz, D, Marschner, J, Orinska, Z & Kaufmann, SHE et al. 2024, 'Sex differences in vaccine induced immunity and protection against <em>Mycobacterium tuberculosis</em>', Biorxiv, S. 2024.04.20.590403. https://doi.org/10.1101/2024.04.20.590403
2023
Chen, J, Wang, X, Schmalen, A, Haines, S, Wolff, M, Ma, H, Zhang, H, Stoleriu, MG, Nowak, J, Nakayama, M, Bueno, M, Brands, J, Mora, AL, Lee, JS, Krauss-Etschmann, S, Dmitrieva, A, Frankenberger, M, Hofer, TP, Noessner, E, Moosmann, A, Behr, J, Milger, K, Deeg, CA, Staab-Weijnitz, CA, Hauck, SM, Adler, H, Goldmann, T, Gaede, KI, Behrends, J, Kammerl, IE & Meiners, S 2023, 'Antiviral CD8+ T cell immune responses are impaired by cigarette smoke and in COPD', The European respiratory journal, Jg. 62, Nr. 2, 2201374. https://doi.org/10.1183/13993003.01374-2022
Farr, A, Cuevas Ocaña, S, Gille, T, Pinnock, H, Bonsignore, MR, Roche, N, Laveneziana, P, Costello, RW, Harari, S, Meiners, S, Loukides, S & Cruz, J 2023, 'What to expect from the ERS International Congress 2023', Breathe, Jg. 19, Nr. 2, S. 230107. https://doi.org/10.1183/20734735.0107-2023
Javitt, A, Shmueli, MD, Kramer, MP, Kolodziejczyk, AA, Cohen, IJ, Radomir, L, Sheban, D, Kamer, I, Litchfield, K, Bab-Dinitz, E, Zadok, O, Neiens, V, Ulman, A, Wolf-Levy, H, Eisenberg-Lerner, A, Kacen, A, Alon, M, Rêgo, AT, Stacher-Priehse, E, Lindner, M, Koch, I, Bar, J, Swanton, C, Samuels, Y, Levin, Y, da Fonseca, PCA, Elinav, E, Friedman, N, Meiners, S & Merbl, Y 2023, 'The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC', Nature cancer, Jg. 4, Nr. 5, S. 629-647. https://doi.org/10.1038/s43018-023-00557-4
Wang, X, Zhang, H, Wang, Y, Bramasole, L, Guo, K, Mourtada, F, Meul, T, Hu, Q, Viteri, V, Kammerl, I, Konigshoff, M, Lehmann, M, Magg, T, Hauck, F, Fernandez, IE & Meiners, S 2023, 'DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity', EMBO JOURNAL , Jg. 42, Nr. 8, S. e110597. https://doi.org/10.15252/embj.2022110597
2022
Bramasole, L & Meiners, S 2022, 'Profiling Proteasome Activities in Peripheral Blood – A Novel Biomarker Approach', Journal of cellular Immunology, Jg. 4, Nr. 5, S. 171-179. https://www.scientificarchives.com/public/assets/articles/article-pdf-1668627159-888.pdf
Kammerl, IE, Hardy, S, Flexeder, C, Urmann, A, Peierl, J, Wang, Y, Vosyka, O, Frankenberger, M, Milger, K, Behr, J, Koch, A, Merl-Pham, J, Hauck, SM, Pilette, C, Schulz, H & Meiners, S 2022, 'Activation of immune cell proteasomes in peripheral blood of smokers and COPD patients - implications for therapy', The European respiratory journal, Jg. 59, Nr. 3, 2101798. https://doi.org/10.1183/13993003.01798-2021
Meiners, S, Yazgili, A & Ebstein, F 2022, 'The proteasome activator PA200/PSME4: an emerging new player in health and disease', Biomolecules, Jg. 12, Nr. 8, S. 1150. https://doi.org/10.3390/biom12081150
Nsiah-Dosu, S, Scholz, C, Orinska, Z, Sadik, CD, Ludwig, RJ, Schmidt, E, Zillikens, D & Hartmann, K 2022, 'Mast cell-deficient mice Mcpt5Cre/Dicerfl/fl redefine the role of mast cells in experimental bullous pemphigoid', Skin Health and Disease, Jg. 2, Nr. 1, e70, S. e70. https://doi.org/10.1002/ski2.70
Schlesser, C, Meul, T, Stathopoulos, G & Meiners, S 2022, 'Metformin Induces Resistance of Cancer Cells to the Proteasome Inhibitor Bortezomib', Biomolecules, Jg. 12, Nr. 6, 756. https://doi.org/10.3390/biom12060756
Zambusi, A, Novoselc, KT, Hutten, S, Kalpazidou, S, Koupourtidou, C, Schieweck, R, Aschenbroich, S, Silva, L, Yazgili, AS, van Bebber, F, Schmid, B, Möller, G, Tritscher, C, Stigloher, C, Delbridge, C, Sirko, S, Günes, ZI, Liebscher, S, Schlegel, J, Aliee, H, Theis, F, Meiners, S, Kiebler, M, Dormann, D & Ninkovic, J 2022, 'TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury', Nature neuroscience, Jg. 25, Nr. 12, S. 1608-1625. https://doi.org/10.1038/s41593-022-01199-y
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