Περίληψη:
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. © 2016 Elsevier Inc.
Συγγραφείς:
Herrtwich, L.
Nanda, I.
Evangelou, K.
Nikolova, T.
Horn, V.
Sagar
Erny, D.
Stefanowski, J.
Rogell, L.
Klein, C.
Gharun, K.
Follo, M.
Seidl, M.
Kremer, B.
Münke, N.
Senges, J.
Fliegauf, M.
Aschman, T.
Pfeifer, D.
Sarrazin, S.
Sieweke, M.H.
Wagner, D.
Dierks, C.
Haaf, T.
Ness, T.
Zaiss, M.M.
Voll, R.E.
Deshmukh, S.D.
Prinz, M.
Goldmann, T.
Hölscher, C.
Hauser, A.E.
Lopez-Contreras, A.J.
Grün, D.
Gorgoulis, V.
Diefenbach, A.
Henneke, P.
Triantafyllopoulou, A.
Λέξεις-κλειδιά:
Myc protein; myeloid differentiation factor 88; protein p53; toll like receptor; toll like receptor 2; ATM protein; lipoprotein; Myc protein; Tlr2 protein, mouse; toll like receptor 2, adult; aged; animal cell; animal experiment; animal model; animal tissue; Article; carcinogenesis; cell differentiation; cell division; cell fate; cell function; cell fusion; cell proliferation; clinical article; controlled study; cytokinesis; DNA content; DNA damage response; DNA replication; DNA synthesis; female; genomic instability; human; human tissue; intracellular signaling; liver granuloma; macrophage; male; mitosis; mouse; nonhuman; polyploidy; priority journal; animal; C57BL mouse; DNA damage; granuloma; immunology; inflammation; macrophage; metabolism; Mycobacterium tuberculosis, Animals; Ataxia Telangiectasia Mutated Proteins; Cell Differentiation; Cell Proliferation; DNA Damage; Granuloma; Humans; Inflammation; Lipoproteins; Macrophages; Mice; Mice, Inbred C57BL; Mitosis; Mycobacterium tuberculosis; Proto-Oncogene Proteins c-myc; Toll-Like Receptor 2
