Mycobacteria exploit nitric oxide‐induced transformation of macrophages into permissive giant cells

Gharun, Kourosh; Senges, J; Seidl, Maximilian; Lösslein, Anne; Kolter, Julia; Lohrmann, Florens; Fliegauf, Manfred; Elgizouli, Magdeldin; Alber, Marco; Vavra, Martina; Illert, Anna Lena; Gilleron, Martine; Kirschning, Carsten J.; Triantafyllopoulou, Antigoni; Henneke, Philipp

doi:10.15252/embr.201847190

Cited by 6 publications

(4 citation statements)

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“…The data supported prior work in cancer cell lines suggesting that growth factor signaling may be a pathway to overcome p53-mediated restrictions to the proliferation of tetraploids [98]. In agreement, BMDM treated with TLR2 ligands showed increased p53 expression [55] and p53 deficient BMDM formed significantly more multinucleated cells following treatment with TLR2 ligands. These data suggest that bacterial lipoproteins induce replication stress and activate p53 that acts to limit multinucleation and polyploidy.…”

Section: Figure 4: Nucleic Acid Metabolic Pathways Control Antiviral ...supporting

confidence: 87%

“…It is possible though that the role of ROS vs NO and/or peroxynitrite changes over time, with ROS mediating oxidative stress early, while NO and/or peroxynitrite may potentially contribute to the activation of the DDR following chronic stimulation with inflammatory ligands (Figure 3C). Indeed, treating BMDM with an NO donor induced increased γH2AX levels [55]. It is important to note that only two of the above studies have demonstrated dsDNA breaks with a comet assay [48,54], raising the possibility that mitochondrial ROS-mediated genotoxic stress may be induced by other forms of DNA damage.…”

Section: Bacteria Induced Genotoxic Stress Via No and Atm Promotes In...mentioning

confidence: 97%

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Genotoxic stress signalling as a driver of macrophage diversity

Kasapi¹,

Triantafyllopoulou²

2022

CST

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Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evidence suggests that macrophage responses to genotoxic stress are embedded in their ‘physiologic’ immune and tissue healing programs and in most cases do not lead to myeloid malignancies. The role of genotoxic stress as an instructor of macrophage-mediated immune defense and tissue remodeling is only beginning to be understood. Here, we review the evidence showing that genotoxic stress, which macrophages and their precursors face upon encountering inflammatory and/or growth signals, instructs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Response (DDR)-driven signaling pathways. We propose that immune-cell specific, DDR-instructed programs are crucial for tissue homeostasis as well as for the maintenance and resolution of inflammatory responses in infection, cancer, autoinflammatory and autoimmune microenvironments.

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Section: Figure 4: Nucleic Acid Metabolic Pathways Control Antiviral ...supporting

confidence: 87%

Section: Bacteria Induced Genotoxic Stress Via No and Atm Promotes In...mentioning

confidence: 97%

Genotoxic stress signalling as a driver of macrophage diversity

Kasapi¹,

Triantafyllopoulou²

2022

CST

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“…Up-to-date, DLK1 along with MKRN3 are two of the four known monogenic causes of CPP and that are both imprinted. This elevates the possibility of imprinting to play a significant role in the regulation of puberty and that other imprinted genes might also be involved in the pubertal control (9,48). Interestingly, the previously reported single nucleotide polymorphism (SNP) rs10407968 (p.Gly8=) in KISS1R gene (49) was detected with a minor allelic frequency (MAF) of 8.33 in the CPP cohort of patients of the present study.…”

Section: Discussionmentioning

confidence: 43%

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty

et al. 2021

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BackgroundCentral precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP.MethodsFifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed.ResultsThree previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP.ConclusionThe results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.

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“…Similarly, MGCs of the adipose tissue (or adipoclasts) can phagocytose lipid remnants more efficiently when they are multinucleated (Braune et al, 2021), a feature that is shared with FBGCs which are also specialized in the uptake of relatively large particles (Milde et al, 2015). However, these findings do not explain why LGCs are multinucleated in granulomas as these MGCs have been described to allow persistence to mycobacterium rather than exerting bactericidal activities (Gharun et al, 2017). Regarding osteoclasts, although fusion confers resorptive function, recent evidence points toward a previously unappreciated plasticity of mature osteoclasts during inflammation (Madel et al, 2019(Madel et al, , 2020.…”

Section: Discussionmentioning

confidence: 96%

Multinucleation resets human macrophages for specialized functions at the expense of their identity

et al. 2023

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Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.

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Mycobacteria exploit nitric oxide‐induced transformation of macrophages into permissive giant cells

Cited by 6 publications

References 0 publications

Genotoxic stress signalling as a driver of macrophage diversity

Genotoxic stress signalling as a driver of macrophage diversity

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty

Multinucleation resets human macrophages for specialized functions at the expense of their identity

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