The focus of our research is to understand the role of distinct programmed cell death pathways in regulating innate immunity, within the gastrointestinal compartment. Unique to our group is the focus on dissecting the contribution of cell death of specific innate immune subsets (dendritic cells) and epithelial cells (Paneth and stem cells) to tissue homeostasis. We also dissect the control of cell-death induction by both TNF receptors by studying their regulation by ubiquitylation events. This research is important for understanding human disease states, namely inflammatory disease (IBD). We achieve these goals via the use of multiple murine in vivo models, in vitro immune cell model systems, state-of-the-art molecular, proteomic, and transcriptional tools, and bioinformatical analysis of human-derived data.
We have shown that specific myeloid cells, namely TLR5+ Type II dendritic cells, as well as epithelial Paneth cells, are more sensitive to undergoing inflammatory cell death in vivo. These findings were made using the murine model for XIAP-deficiency, which is the genetic cause of human immunodeficiency. Current research is focused on defining the unique factors that define TLR5+cDC2 and their function within the intestinal lamina propria of mice. This work is based on our findings that TLR5+ type II dendritic cells (cDC2) are depleted in the small intestine of inflamed Xiap-/- mice in a TNFR2-dependent manner. Thus, we postulate that the sensitivity to undergo cell death in these cells is differentially regulated compared to other myeloid cell types in this local environment. We are also working to further define how the changes in the innate immune subsets impact T-cell functions, specifically in the small intestine. We are also interested in dissecting the Microbial triggers of intestinal inflammation in XIAP-deficient hosts. This is within CRC1371 “Microbiome Signatures”.
Griewahn, L., Müller-Foxworth, M., Peintner, L., Wissler, M., Weiss, M., Brauns-Schubert, P., Massoumi, R., Borner, C., Groß, O., Yabal, M., Charvet, C., and Maurer, U. (2023) SPATA2 restricts OTULIN-dependent LUBAC activity independently of CYLD. Cell Rep.42, 111961
Wahida, A., Müller, M., Hiergeist, A., Popper, B., Steiger, K., Branca, C., Tschurtschenthaler, M., Engleitner, T., Donakonda, S., De Coninck, J., Öllinger, R., Pfautsch, M. K., Müller, N., Silva, M., Usluer, S., Oberg, E. T., Böttcher, J. P., Pfarr, N., Anton, M., Slotta-Huspenina, J. B., Nerlich, A. G., Madl, T., Basic, M., Bleich, A., Berx, G., Ruland, J., Knolle, P. A., Rad, R., Adolph, T. E., Vandenabeele, P., Kanegane, H., Gessner, A., Jost, P. J., and Yabal, M. (2021) XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells. Sci. Immunol. 6, eabf7235
Stafford, C. A., Gassauer, A.-M., de Oliveira Mann, C. C., Tanzer, M. C., Fessler, E., Wefers, B., Nagl, D., Kuut, G., Sulek, K., Vasilopoulou, C., Schwojer, S. J., Wiest, A., Pfautsch, M. K., Wurst, W., Yabal, M., Fröhlich, T., Mann, M., Gisch, N., Jae, L. T., and Hornung, V. (2022) Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation. Nature 609, 590–596
Lawlor, K. E.*, Feltham, R.*, Yabal*, M., Conos, S. A., Chen, K. W., Ziehe, S., Graß, C., Zhan, Y., Nguyen, T. A., Hall, C., Vince, A. J., Chatfield, S. M., D’Silva, D. B., Pang, K. C., Schroder, K., Silke, J., Vaux, D. L., Jost, P. J., and Vince, J. E. (2017) XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation. Cell Rep. 20, 668–682
Höckendorf, U., Yabal, M., Herold, T., Munkhbaatar, E., Rott, S., Jilg, S., Kauschinger, J., Magnani, G., Reisinger, F., Heuser, M., Kreipe, H., Sotlar, K., Engleitner, T., Rad, R., Weichert, W., Peschel, C., Ruland, J., Heikenwalder, M., Spiekermann, K., Slotta-Huspenina, J., Groß, O., and Jost, P. J. (2016) RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells. Cancer Cell 30, 75–91
Yabal, M., Müller, N., Adler, H., Knies, N., Groß, C. J., Damgaard, R. B., Kanegane, H., Ringelhan, M., Kaufmann, T., Heikenwälder, M., Strasser, A., Groß, O., Ruland, J., Peschel, C., Gyrd-Hansen, M., and Jost, P. J. (2014) XIAP Restricts TNF- and RIP3-Dependent Cell Death and Inflammasome Activation. Cell Rep. 7, 1796–1808
Damgaard, R. B.*, Nachbur, U.*, Yabal, M.*, Wong, W. W.-L., Fiil, B. K., Kastirr, M., Rieser, E., Rickard, J. A., Bankovacki, A., Peschel, C., Ruland, J., Bekker-Jensen, S., Mailand, N., Kaufmann, T., Strasser, A., Walczak, H., Silke, J., Jost, P. J., and Gyrd-Hansen, M. (2012) The Ubiquitin Ligase XIAP Recruits LUBAC for NOD2 Signaling in Inflammation and Innate Immunity. Mol. Cell 46, 746–758
The current list of our publications can be found on Pubmed.
We are supported by the CRC1371 "Microbiome Signatures", the TRR353 "Cell death decisions" and the DFG. We are also supported by the BMBF.