DNA damage signaling instructs polyploid macrophage fate in granulomas
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 MH, Wagner D, Dierks C, Haaf T, Ness T, Zaiss MM, Voll RE, Deshmukh SD, Prinz M, Goldmann T, Hölscher C, Hauser AE, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, Triantafyllopoulou A.
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. 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.
