DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

Herrtwich, Laura; Nanda, Indrajit; Evangelou, Konstantinos; Nikolova, Teodora; Horn, Veronika; Sagar,; Erny, Daniel; Stefanowski, Jonathan; Rogell, Leif; Klein, C.; Gharun, Kourosh; Follo, Marie; Seidl, Maximilian; Kremer, Bernhard; Münke, Nikolas; Senges, J; Fliegauf, Manfred; Aschman, Tom; Pfeifer, Dietmar; Sarrazin, Sandrine; Sieweke, Michael H.; Wagner, Dirk; Dierks, Christine; Haaf, Thomas; Neß, Thomas; Zaiss, Mario M.; Voll, Reinhard; Deshmukh, S. D.; Prinz, Marco; Goldmann, Torsten; Hölscher, Christoph; Hauser, Anja E.; López-Contreras, Andrés J.; Grün, Dominic; Gorgoulis, Vassilis G.; Diefenbach, Andreas; Henneke, Philipp; Triantafyllopoulou, Antigoni

doi:10.1016/j.cell.2018.08.015

Cited by 10 publications

(2 citation statements)

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“…However, it is important to note that colony stimulating factor proteins have recently been shown-in a membrane fusion-independent manner-to stimulate the formation of multinucleated giant cells (MGCs), which are key components of TB-induced granulomas. For example, CSF1 in conjunction with a persistent ligand, such as TNF, can induce MGCs from bone marrow myeloid progenitors via polyploidy, typically associated with replication stress or DNA damage (Herrtwich et al 2018), which supports a larger role for CSF proteins in the formation of TB granulomas. In addition, our group has recently shown that the CSF3 locus is epigenetically regulated through H3K4me3 deposition in bovine AM infected with M. bovis (Hall et al 2020).…”

Section: Genes Enriched For Btb and Htb Gwas Snps In Both Species Pla...mentioning

confidence: 93%

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

Hall

McHugo

Mullen

et al. 2023

Preprint

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Mycobacterium tuberculosis, the causative agent of human tuberculosis (hTB), is currently classed as the thirteenth leading cause of death worldwide. Mycobacterium bovis, a close evolutionary relative of M. tuberculosis, causes bovine tuberculosis (bTB) and is one of the most damaging infectious diseases to livestock agriculture. Previous studies have shown that the pathogenesis of bTB disease is comparable to hTB disease, and that the bovine and human alveolar macrophage (bAM and hAM, respectively) transcriptomes are extensively reprogrammed in response to infection with these intracellular mycobacterial pathogens. However, although M. bovis and M. tuberculosis share over 99% identity at the genome level, the innate immune responses to these pathogens have been shown to be different in human or cattle hosts. In this study, a multi-omics integrative approach was applied to encompass functional genomics and GWAS data sets across the two primary hosts (Bos taurus and Homo sapiens) and both pathogens (M. bovis and M. tuberculosis). Four different experimental infection groups were used, each with parallel non-infected control cells: 1) bAM infected with M. bovis, 2) bAM infected with M. tuberculosis, 3) hAM infected with M. tuberculosis, and 4) human monocyte-derived macrophages (hMDM) infected with M. tuberculosis. RNA-seq data from these experiments 24 hours post-infection (24 hpi) was analysed using three separate computational pipelines: 1) differentially expressed genes, 2) differential gene expression interaction networks, and 3) combined pathway analysis. The results of these analyses were then integrated with high-resolution bovine and human GWAS data sets to detect novel quantitative trait loci (QTLs) for resistance to mycobacterial infection and resilience to disease. Results from this study revealed common and unique response macrophage pathways for both pathogens and identified 32 genes (12 bovine and 20 human) significantly enriched for SNPs associated with disease resistance, the majority of which encode key components of the NF-κB signalling pathway and that also drive formation of the granuloma.

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Section: Genes Enriched For Btb and Htb Gwas Snps In Both Species Pla...mentioning

confidence: 93%

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

Hall

McHugo

Mullen

et al. 2023

Preprint

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show abstract

“…In this case, ATM also appears to regulate immune gene expression in injured macrophages. Other DDR components, such as NBS1 and ATR, also have been shown to play a necessary part in normal macrophage proliferation and differentiation [146,[217][218][219][220]. Furthermore, it has been demonstrated that the IFN-STAT1 pathway functions as an effector of DDR components in cancer cells by inhibiting flap endonuclease-1 (FEN1), which affects human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1) to suppress the tumorigenesis dependent on the IFN-γ-JAK-STAT1 pathway in oral squamous cell carcinoma [221].…”

Section: The Roles Of Ddr In the Immune-stimulatory Capacity Of Antig...mentioning

confidence: 99%

When DNA-damage responses meet innate and adaptive immunity

Tong,

Song,

Zhang

et al. 2024

Cell. Mol. Life Sci.

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When cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)–Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network’s immune modulators’ dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.

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Der Rolle der DNA-Schadensantwort bei granulomatösen Erkrankungen

Fabry

Triantafyllopoulou

2022

Z Rheumatol

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ZusammenfassungGranulome sind organisierte Aggregate von Immunzellen, die sich infolge eines persistierenden Stimulus bilden und bei verschiedenen rheumatischen Erkrankungen zu finden sind. Zentraler Bestandteil von Granulomen ist eine Vielzahl unterschiedlicher Makrophagensubtypen. Darunter befinden sich auch multinukleäre Makrophagen, die mehrere Zellkerne aufweisen. Die genauen Mechanismen, welche die Granulomentstehung vermitteln, sind bislang noch nicht vollständig aufgeklärt. Neuere Daten zeigen jedoch, dass die DNA-Schadensantwort eine relevante Rolle bei der Entstehung multinukleärer Makrophagen und damit bei der Bildung von Granulomen spielen könnte.

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DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

Cited by 10 publications

References 0 publications

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

Integrative and comparative genomic analyses of mammalian macrophage responses to intracellular mycobacterial pathogens

When DNA-damage responses meet innate and adaptive immunity

Der Rolle der DNA-Schadensantwort bei granulomatösen Erkrankungen

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