FOR2599Project 1

Regulation of type 2 immunity mediated at the level of macrophage polarization

Peter J. Murray, Max-Planck-Institut für Biochemie, Martinsried

Summary

TNF is a central pro-inflammatory cytokine involved in a myriad of inflammatory pathologies and targeted by anti-TNF biologic drugs. We discovered that TNF inhibits wound healing and tissue reparative macrophages induced by type 2 cytokines (IL4 and IL13). We predict that understanding the relationships between cytokines that control macrophages necessary for tissue homeostasis will give new insights into pathophysiology. The goal of this project is therefore to identify the TNF-dependent TF that negatively regulate the IL4+IL13-induced genes linked to wound healing, tissue repair and immune regulation. Second, we will place the identified TF in the wider context of type 2 tissue immunity by expression and functional studies in collaboration with multiple members of the FOR 2599 team. IL4+IL13 induces the expression of hundreds of mRNAs in stimulated macrophages. By contrast, we found TNF’s effects are highly specific and targeted, via a transcriptional process, only a small fraction of these mRNAs are suppressed. A striking observation is, however, that many of the mRNAs encode known proteins involved in the linked processes of wound and tissue repair and immune regulation. Therefore, the hypothesis we will test in this objective is that TNF’s main function in type 2 immune regulation is to selectively target a fraction of genes collectively necessary to complete the pro-resolving functions of the type 2 immune program (temporally, and in the steady state). A related hypothesis is that excess or dysregulated TNF will block specific components of type 2 immunity via specific TF expression. Ergo, the key step to testing these hypotheses is to isolate the relevant TF and test their ability in loss- and gain-of-function experiments to target IL4+IL13-regulated genes.

Selected Publications

Metabolic orchestration of the wound healing response. Sabine A. Eming*, Peter J. Murray*, Edward J. Pearce* Cell Metabolism (2021) In Press. *Equal authorship

Neuroblastoma formation requires unconventional CD4 T cells and Arginase-1-dependent myeloid cells. Lee-Ann Van de Velde, E. Kaitlynn Allen, Jeremy Chase Crawford, Taylor  Wilson, CliffordS. Guy, Marion Russier, Leonie Zeitler, Armita Bahrami, David Finkelstein, Stephane Pelletier, Stacey Schultz-Cherry, Paul G. Thomas and Peter J. Murray Cancer Res (2021) DOI:10.1158/0008-5472.CAN-21-0691 (In press online first manuscript)

Lactate and IL6 define separable paths of inflammatory metabolic adaptation Dichtl, S., L. Lindenthal, L. Zeitler, K. Behnke, D. Schlosser, B. Strobl, J. Scheller, K. C. El Kasmi and P. J. Murray Sci Adv  (2021) 7:eabg3505.  https://www.ncbi.nlm.nih.gov/pubmed/34162546

Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism Zeitler, L., A. Fiore, C. Meyer, M. Russier, G. Zanella, S. Suppmann, M. Gargaro, S. S. Sidhu, S. Seshagiri, C. Ohnmacht, T. Kocher, F. Fallarino, A. Linkermann and P. J. Murray eLife  (2021) 10:e64806. https://www.ncbi.nlm.nih.gov/pubmed/33646117

The Disabled homolog 2 controls pro-metastatic activity of tumor-associated macrophages Marigo, I., R. Trovato, F. Hofer, V. Ingangi, D. E. S. F, S. Ugel, S. Cane, A. Simonelli, A. Lamolinara, M. Iezzi, M. Fassan, M. Rugge, F. Boschi, G. Borile, T. Eisenhaure, S. Sarkizova, D. Lieb, N. Hacohen, L. Azzolin, S. Piccolo, R. Lawlor, A. Scarpa, L. Carbognin, E. Bria, S. Bicciato, P. J. Murray and V. Bronte Cancer Discov  (2020). 10: 1758.https://cancerdiscovery.aacrjournals.org/content/10/11/1758.long