L-MAC: Probing the STAT impact on homeostatic lung macrophage signatures

NETWORK CONTRIBUTION

Macrophages are prototypic resident immune cells that shape a range of effects, from safeguarding homeostasis to inflammation, based on their remarkable plasticity and ability to adjust quickly to changing environmental cues. A panel of transcription factors and epigenetic regulators in conjunction with STAT1/3/6 define the state of the resident macrophages. Recent advances in transcriptional and chromatin profiling have opened an entirely new avenue to investigate the environmental cues that define tissue-specific macrophage profiles in health and their dynamics upon stress/disease.

Our major goal is to analyse the role of STAT1/3 in the in vivo homeostatic signature of alveolar macrophages (AM) and to investigate the hierarchy of changes on acute perturbations of homeostasis (such as after birth). We shall determine the transcriptional profile (RNASeq) and enhancer landscape of healthy adult pulmonary macrophages by genome-wide mapping of selected histone marks and open chromatin (Chip-Seq, ATAC-Seq).

Within the project part we aim to derive a detailed map of transcriptional and enhancer landscapes of AMs, and insights into the role of STAT1/3, will provide an excellent basis for understanding the memory potential and functional impact of perturbations and will open ways to develop drugs to modulate macrophage activity in inflammatory diseases.

PUBLICATIONS

SFB-F61 / F28 related publications - Group Knapp

Radwan*, M., Stiefvater*, R., Grunert, T., Sharif, O., Miller, I., Marchetti-Deschmann, M., Allmaier, G., Gemeiner, M., Knapp, S., Kovarik§, P., Müller, M., and Strobl, B. (2010). *equal contribution §SFB member of the 1st funding period
Tyrosine kinase 2 controls IL-1beta production at the translational level.
J Immunol 185: 3544-3553. doi: 10.4049/jimmunol.0904000
Gratz, N., Hartweger, H., Matt, U., Kratochwill, F., Janos, M., Sigel, S., Drobits, B., Li, X.-D., Knapp, S., and Kovarik§, P. (2011). §SFB member of the 1st funding period
Type I Interferon Production Induced by Streptococcus pyogenes-Derived Nucleic Acids Is Required for Host Protection.
PLoS Pathog 7: e1001345. doi: 10.1371/journal.ppat.1001345
Laimer, D., Dolznig, H., Kollmann, K., Vesely, P.W., Schlederer, M., Merkel, O., Schiefer, A.-I., Hassler, M.R., Heider, S., Amenitsch, L., Thallinger, C., Staber, P.B., Simonitsch-Klupp, I., Artaker, M., Lagger, S., Pileri, S., Piccaluga, P.P., Valent, P., Messana, K., Landra, I., Weichhart, T., Knapp, S., Shehata, M., Todaro, M., Sexl, V., Höfler, G., Piva, R., Medico, E., Riggeri, B.A., Cheng, M., Eferl, R., Egger, G., Penninger, J.M., Jaeger, U., Moriggl, R., Inghirami, G., and Kenner, L. (2012).
PDGFR blockade is a rational and effective therapy for NPM-ALK–driven lymphomas.
Nat Med 18: 1699-1704. doi: 10.1038/nm.2966
Warszawska, J.M., Gawish, R., Sharif, O., Sigel, S., Doninger, B., Lakovits, K., Mesteri, I., Nairz, M., Boon, L., Spiel, A., Fuhrmann, V., Strobl, B., Müller, M., Schenk, P., Weiss, G., and Knapp, S. (2013).
Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes.
J Clin Invest 123: 3363-3372. doi: 10.1172/JCI67911
Castiglia, V., Piersigilli, A., Ebner, F., Janos, M., Goldmann, O., Dambock, U., Kroger, A., Weiss, S., Knapp, S., Jamieson, A.M., Kirschning, C., Kalinke, U., Strobl, B., Muller, M., Stoiber, D., Lienenklaus, S., and Kovarik, P. (2016).
Type I Interferon Signaling Prevents IL-1beta-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue.
Cell Host Microbe 19, 375-387
Maier, B.B., Hladik, A., Lakovits, K., Korosec, A., Martins, R., Kral, J.B., Mesteri, I., Strobl, B., Muller, M., Kalinke, U., Merad, M., and Knapp, S. (2016).
Type I interferon promotes alveolar epithelial type II cell survival during pulmonary S. pneumoniae infection and sterile lung injury in mice.
European journal of immunology 10.1002/eji.201546201
Martins, R., and Knapp, S. (2017).
Heme and hemolysis in innate immunity: adding insult to injury.
Curr Opin Immunol 50, 14-20

TEAM