6533b852fe1ef96bd12ab90a
RESEARCH PRODUCT
DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas.
Thomas HaafDaniel ErnyLaura HerrtwichDirk WagnerTorsten GoldmannMarie FolloDietmar PfeiferChristoph HölscherReinhard E. VollDominic GrünSachin D. DeshmukhThomas NessMarco PrinzTeodora NikolovaBernhard KremerVassilis G. GorgoulisKonstantinos EvangelouAnja E. HauserIndrajit NandaJonathan StefanowskiClaudius KleinChristine DierksMichael H. SiewekeAntigoni TriantafyllopoulouManfred FliegaufLeif RogellLeif RogellTom AschmanAndreas DiefenbachSandrine SarrazinSagarAndrés J. López-contrerasNikolas MünkeJulia SengesMario M. ZaissPhilipp HennekeVeronika HornMaximilian SeidlKourosh Gharunsubject
0301 basic medicineGenome instabilityDNA damageLipoproteinsCellMitosisInflammationAtaxia Telangiectasia Mutated ProteinsBiologymedicine.disease_causeGeneral Biochemistry Genetics and Molecular BiologyProto-Oncogene Proteins c-myc03 medical and health sciencesMicemedicineAnimalsHumansMacrophage Differentiation PathwayMitosisCell ProliferationInflammationGranulomaMacrophagesCell DifferentiationMycobacterium tuberculosisToll-Like Receptor 2Cell biologyMice Inbred C57BLTLR2030104 developmental biologymedicine.anatomical_structureImmunologymedicine.symptomCarcinogenesisDNA Damagedescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-08-01 | Cell |