Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain

Sahasrabuddhe, Vinaya; Ghosh, Hiyaa S.

doi:10.1016/j.celrep.2021.110252

Cited by 59 publications

(51 citation statements)

References 66 publications

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“…In addition, the proinflammatory markers, such as CD16, CCL3, IL-1β and TNF-α increased in Sirt3 f/f Cx3cr1-Cre mice compared with Sirt3 f/f mice at day 3 after ICH, while the anti-inflammatory markers decreased at day7, suggesting that IF may act through microglial Sirt3 to manipulate neuroinflammation after ICH. It is worth noting, though, Cx3cr1-driven Cre recombinase is a widely used genetic tool for enabling gene manipulation in microglia [36,37], nonmicroglial cells expressing Cx3cr1, such as macrophage and leakiness of cre activity into neurons have become a major concern [38]. In the present study, conditional knockout of Sirt3 in cells with Cx3cr1 promoter attenuated the protective effects of IF.…”

Section: Discussionmentioning

confidence: 50%

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Dai

Wei

Zhang

et al. 2022

J Neuroinflammation

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Background Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown to be protective against inflammation in multiple pathogenic processes. In the present study, we aimed to investigated the beneficial effects of IF in attenuating neuroinflammation and neurological deficits in a mouse model of ICH and to investigate the underlying mechanism. Methods ICH was modeled by intrastriatal injection of autologous blood and IF was modeled by every-other-day feeding in male control mice (C57BL/6), mice with and microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), and Sirt3f/f (wild-type) mice. Brain tissues and arterial blood were harvested at 1, 3, 7 and 28 days after ICH for immunohistochemistry analysis of Iba-1, DARPP-32 and HO-1, morphological analysis by HE staining and inflammatory factor release tests by ELISA. Neurological functions were approached by corner test and cylinder test. Fluorescent double-labeled staining of Iba-1 with CD16, Arg1 or Sirt3 was used to provide direct image of co-expression of these molecules in microglia. TUNEL, cleaved caspase-3 and Nissl staining was performed to evaluate cellular injuries. Results IF alleviated neurological deficits in both acute and chronic phases after ICH. Morphologically, IF enhanced hematoma clearance, reduced brain edema in acute phase and attenuated striatum atrophy in chronic phase. In addition, IF decreased the numbers of TUNEL+ cells and increased Nissl+ neuron number at day 1, 3 and 7 after ICH. IF suppressed CD16+Iba-1+ microglia activation at day 3 after ICH and reduced inflammatory releases, such as IL-1β and TNF-α. The above effects of IF were attenuated by microglia Sirt3 deletion partly because of an inhibition of Nrf2/HO-1 signaling pathway. Interestingly, IF increased Iba-1+ microglia number at day 7 which mainly expressed Arg1 while decreased the proinflammatory factor levels. In mice with microglia-specific Sirt3 deletion, the effects of IF on Iba-1+ microglia activation and anti-inflammatory factor expressions were attenuated when compared with wild-type Sirt3f/f mice. Conclusions IF protects against ICH by suppressing the inflammatory responses via the Sirt3/Nrf2/HO-1 pathway.

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Section: Discussionmentioning

confidence: 50%

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Dai

Wei

Zhang

et al. 2022

J Neuroinflammation

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“…Each consideration is rated on a scale from low (-) to high (++++), not tested (?). 1(Parkhurst et al, 2013), 2(Yona et al, 2013), 3(Goldmann et al, 2016), 4 (Kaiser and Feng, 2019), 5(Masuda et al, 2020), 6 (Sahasrabuddhe and Ghosh, 2022) from Jackson Laboratories (Bar Harbor, ME).…”

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confidence: 99%

A comparative analysis of microglial inducible Cre lines

Faust

Feinberg

O’Connor

et al. 2023

Preprint

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Cre/LoxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. The field of microglial biology has particularly benefited from this technology as microglia have historically been difficult to transduce with virus or electroporation methods for gene delivery. Here, we interrogate four of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency and spontaneous recombination, depending on the Cre line and loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency in microglia, which could be extended to other cell types. There is increasing evidence that microglia are key regulators of neural circuit structure and function. Microglia are also major drivers of a broad range of neurological diseases. Thus, reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field of microglial biology and the development of microglia-based therapeutics.

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“…No visible changes in individual development were observed in Cx3cr1 Cre/+ Rbpj fl/fl embryonic mice. We excluded the influence of Cx3cr1-Cre 43 in embryonic microglial development, according to the paralleled populations of IBA1 + and F4/80 + cells, the percentage of CD11b hi CD45 lo microglia, and their gene expression in the mesencephalic regions among Rbpj fl/fl , Cx3cr1 Cre/+ , and WT mice (Fig. 8c, d , Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Brain milieu induces early microglial maturation through the BAX-Notch axis

Zhao

Tang

et al. 2022

Nat Commun

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Microglia are derived from primitive myeloid cells and gain their early identity in the embryonic brains. However, the mechanism by which the brain milieu confers microglial maturation signature remains elusive. Here, we demonstrate that the baxcq55 zebrafish and Baxtm1Sjk mouse embryos exhibit similarly defective early microglial maturation. BAX, a typical pro-apoptotic factor, is highly enriched in neuronal cells and regulates microglial maturation through both pro-apoptotic and non-apoptotic mechanisms. BAX regulates dlb via the CaMKII-CREB axis calcium-dependently in living neurons while ensuring the efficient Notch activation in the immigrated pre-microglia by apoptotic neurons. Notch signaling is conserved in supporting embryonic microglia maturation. Compromised microglial development occurred in the Cx3cr1Cre/+Rbpjfl/fl embryonic mice; however, microglia acquire their appropriate signature when incubated with DLL3 in vitro. Thus, our findings elucidate a BAX-CaMKII-CREB-Notch network triggered by the neuronal milieu in microglial development, which may provide innovative insights for targeting microglia in neuronal disorder treatment.

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Cx3Cr1-Cre induction leads to microglial activation and IFN-1 signaling caused by DNA damage in early postnatal brain

Cited by 59 publications

References 66 publications

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway

A comparative analysis of microglial inducible Cre lines

Brain milieu induces early microglial maturation through the BAX-Notch axis

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