Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

Geiger-Maor, Anat; Guedj, Avital; Even-Ram, Sharona; Smith, Yoav; Galun, Eithan; Rachmilewitz, Jacob

doi:10.1158/0008-5472.can-14-3635

Cited by 18 publications

(26 citation statements)

References 51 publications

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“…In a recent study, we demonstrated in 1-month-old mice that diethylnitrosamine (DEN)-induced DNA damage is resolved within 6 days, reflecting the efficiency of the DNA-repair mechanisms [24]. In the present study we extended this earlier observation to mice of various ages, in order to determine how age affects the extent of DSBs generation and the kinetics of the resolution.…”

Section: Introductionmentioning

confidence: 73%

Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

Guedj

Geiger-Maor

Benyamini³

et al. 2016

Aging

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Aging is associated with progressive decline in cell function and with increased damage to macromolecular components. DNA damage, in the form of double-strand breaks (DSBs), increases with age and in turn, contributes to the aging process and age-related diseases. DNA strand breaks triggers a set of highly orchestrated signaling events known as the DNA damage response (DDR), which coordinates DNA repair. However, whether the accumulation of DNA damage with age is a result of decreased repair capacity, remains to be determined. In our study we showed that with age there is a decline in the resolution of foci containing γH2AX and pKAP-1 in diethylnitrosamine (DEN)-treated mouse livers, already evident at a remarkably early age of 6-months. Considerable age-dependent differences in global gene expression profiles in mice livers after exposure to DEN, further affirmed these age related differences in the response to DNA damage. Functional analysis identified p53 as the most overrepresented pathway that is specifically enhanced and prolonged in 6-month-old mice. Collectively, our results demonstrated an early decline in DNA damage repair that precedes ‘old age’, suggesting this may be a driving force contributing to the aging process rather than a phenotypic consequence of old age.

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Section: Introductionmentioning

confidence: 73%

Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

Guedj

Geiger-Maor

Benyamini³

et al. 2016

Aging

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“…Myeloid cells are recruited to the liver to repair acute DNA damage . We therefore assessed expression levels of inflammatory cytokines 48 hours after an acute DNA damage.…”

Section: Resultsmentioning

confidence: 99%

IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice

et al. 2017

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Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin‐6 (IL‐6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL‐6 classic and the IL‐6 trans‐signaling pathway. Whereas IL‐6 classic signaling is important for innate and acquired immunity, IL‐6 trans‐signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL‐6 trans‐signaling, but not IL‐6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA‐damage‐induced hepatocyte apoptosis through suppression of p53 and enhances β‐catenin activation and tumor proliferation. Second, IL‐6 trans‐signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL‐6 trans‐signaling are largely protected from tumor formation in a diethylnitrosamine/3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene model of HCC. Conclusion: IL‐6 trans‐signaling, and not IL‐6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL‐6 trans‐signaling, rather than total inhibition of IL‐6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL‐6 classic signaling‐driven protective immune responses. (Hepatology 2017;65:89‐103).

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“…To test the efficiency and kinetics of DNA damage repair, we induced DNA damage in mouse livers by a single injection of DEN, as previously described 6 15. We performed immunofluorescence staining to detect cells containing phosphorylated histone H2AX (γH2AX) in liver tissue sections at days 2 and 6 following DEN injection.…”

Section: Resultsmentioning

confidence: 99%

“…Immunohistochemical analysis of liver tissues was performed as described previously 6 15. For more details see online supplementary methods.…”

Section: Methodsmentioning

confidence: 99%

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Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

Guedj

Volman

Geiger-Maor

et al. 2019

Gut

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ObjectiveFailing to properly repair damaged DNA drives the ageing process. Furthermore, age-related inflammation contributes to the manifestation of ageing. Recently, we demonstrated that the efficiency of repair of diethylnitrosamine (DEN)-induced double-strand breaks (DSBs) rapidly declines with age. We therefore hypothesised that with age, the decline in DNA damage repair stems from age-related inflammation.DesignWe used DEN-induced DNA damage in mouse livers and compared the efficiency of their resolution in different ages and following various permutations aimed at manipulating the liver age-related inflammation.ResultsWe found that age-related deregulation of innate immunity was linked to altered gut microbiota. Consequently, antibiotic treatment, MyD88 ablation or germ-free mice had reduced cytokine expression and improved DSBs rejoining in 6-month-old mice. In contrast, feeding young mice with a high-fat diet enhanced inflammation and facilitated the decline in DSBs repair. This latter effect was reversed by antibiotic treatment. Kupffer cell replenishment or their inactivation with gadolinium chloride reduced proinflammatory cytokine expression and reversed the decline in DSBs repair. The addition of proinflammatory cytokines ablated DSBs rejoining mediated by macrophage-derived heparin-binding epidermal growth factor-like growth factor.ConclusionsTaken together, our results reveal a previously unrecognised link between commensal bacteria-induced inflammation that results in age-dependent decline in DNA damage repair. Importantly, the present study support the notion of a cell non-autonomous mechanism for age-related decline in DNA damage repair that is based on the presence of ‘inflamm-ageing’ cytokines in the tissue microenvironment, rather than an intrinsic cellular deficiency in the DNA repair machinery.

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Macrophages Regulate the Systemic Response to DNA Damage by a Cell Nonautonomous Mechanism

Cited by 18 publications

References 51 publications

Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

Early age decline in DNA repair capacity in the liver: in depth profile of differential gene expression

IL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice

Gut microbiota shape ‘inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair

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