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DNA damage signaling instructs polyploid macrophage fate in granulomas

Item Type:Article
Title:DNA damage signaling instructs polyploid macrophage fate in granulomas
Creators Name:Herrtwich, L. and Nanda, I. and Evangelou, K. and Nikolova, T. and Horn, V. and Sagar, and Erny, D. and Stefanowski, J. and Rogell, L. and Klein, C. and Gharun, K. and Follo, M. and Seidl, M. and Kremer, B. and Münke, N. and Senges, J. and Fliegauf, M. and Aschman, T. and Pfeifer, D. and Sarrazin, S. and Sieweke, M.H. and Wagner, D. and Dierks, C. and Haaf, T. and Ness, T. and Zaiss, M.M. and Voll, R.E. and Deshmukh, S.D. and Prinz, M. and Goldmann, T. and Hölscher, C. and Hauser, A.E. and Lopez-Contreras, A.J. and Grün, D. and Gorgoulis, V. and Diefenbach, A. and Henneke, P. and Triantafyllopoulou, A.
Abstract:Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.
Keywords:Macrophages, Granulomas, DNA Damage, Replication Stress, Inflammation, Mycobacteria, Tuberculosis, Animals, Mice
Publisher:Cell Press
Page Range:1264-1280
Date:17 November 2016
Additional Information:Erratum in: Cell 174(5): 1325-1326.
Official Publication:https://doi.org/10.1016/j.cell.2016.09.054
PubMed:View item in PubMed

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