Requirement of DNase II for Definitive Erythropoiesis in the Mouse Fetal Liver

Kawane, Kohki; Fukuyama, Hidehiro; Kondoh, Gen; Takeda, Junji; Ohsawa, Yoshiyuki; Uchiyama, Yasuo; Nagata, Shinji

doi:10.1126/science.292.5521.1546

Cited by 345 publications

(319 citation statements)

References 25 publications

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“…Interestingly, inhibition of the ability of plasmatocytes to engulf bacteria by the prior application of polystyrene beads into the body cavity results in a significant loss of viability in flies carrying a mutation in the humoral response [40]. Interestingly the negative effect mediated by bead accumulation in plasmatocytes resembled the deleterious effect of accumulation of apoptotic nuclei in macrophages of dnase II -/-mice [10]. Due to this resemblance, we predicted that the loss of DNase II activity would result in the accumulation of DNA within phagocytic cells with a concomitant loss of immune function.…”

Section: Discussionmentioning

confidence: 99%

“…Although an increase in antimicrobial peptide production would be expected to partially compensate for the loss of hemocyte function, this was clearly not the case. This perplexing result is reminiscent of the embryonic lethality observed in dnase II-knockout mice which is caused by an unexpected overexpression of INF-β by macrophages [10][11][12]. Apart from antimicrobial peptide induction, it has been demonstrated that dDNase II itself is significantly induced by bacterial and fungal infection [41,42].…”

Section: Discussionmentioning

confidence: 99%

“…Mutation of the C. elegans dnase II homologue, nuc-1, resulted in persistent dead-cell nuclei within neighboring phagocytic cells as well as accumulation of DNA within the gut and ovaries [7,8]. Interestingly, targeted mutation of the dnase II gene in the germline of mice resulted in perinatal lethality presumably due to loss definitive erythropoiesis [9,10]. Subsequent analyses of these mutant mice revealed that dnase II-deficient macrophages accumulate ingested DNA and overexpress β-interferon (INFβ) resulting in embryonic lethality [11,12].…”

Section: Introductionmentioning

confidence: 99%

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DNase II deficiency impairs innate immune function in Drosophila

Seong

Varela-Ramı́rez

Aguilera

2006

Cellular Immunology

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DNase II enzymes are highly conserved proteins that are required for the degradation of DNA within phagolysosomes. Engulfment of apoptotic cells and/or bacteria by phagocytic cells requires the function of DNase II to completely destroy ingested DNA. Mutation of the dnase II gene results in an increase of undegraded apoptotic DNA within phagocytic cells in mice and nematodes. Additionally, reduction of DNase II enzymatic activity in Drosophila melanogaster has been shown to lead to increased accumulation of DNA in the ovaries. Due to the importance of DNA clearance during infection, we hypothesized that a severe reduction of DNase II activity would result in diminished immune function and viability. To test this hypothesis, we knocked down DNase II activity in flies using RNAi. As expected, expression of a dnase II-RNAi construct in flies resulted in a dramatic reduction of DNase II activity and a significant decrease in total hemocyte numbers. Furthermore, infection of dnase II-RNAi flies with Gram negative or positive bacteria resulted in a severe reduction in fly viability. These results confirm that DNase II and the ability to clear macromolecular DNA is essential for maintaining proper immune function in Drosophila.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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DNase II deficiency impairs innate immune function in Drosophila

Seong

Varela-Ramı́rez

Aguilera

2006

Cellular Immunology

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“…DNase II is responsible for digesting the DNA of apoptotic cells after macrophages engulf them, and many macrophages carrying engulfed DNA are present in DNase IIdeficient embryos. [20][21][22] Here, we used DNase II-deficient mice to detect the programmed cell death that occurs during mouse development, and found that Apaf-1 seems to be dispensable for this process. In the thymus of Apaf-1 À/À embryos at E14.5, caspases were activated in an Apaf-1-independent manner.…”

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confidence: 99%

Apaf-1-independent programmed cell death in mouse development

et al. 2009

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Many cells die during mammalian development and are engulfed by macrophages. In DNase II À/À embryos, the TUNEL-positive DNA of apoptotic cells is left undigested in macrophages, providing a system for studying programmed cell death during mouse development. Here, we showed that an Apaf-1-null mutation in the DNase II À/À embryos greatly reduced the number of macrophages carrying DNA at E11.5. However, at later stages of the embryogenesis, a significant number of macrophages carrying undigested DNA were present in Apaf-1 À/À embryos, indicating that cells died and were engulfed in an Apaf-1-independent manner. In most tissues of the Apaf-1 À/À embryos, no processed caspase-3 was detected, and the DNA of dead cells accumulated in the macrophages appeared intact. Many nonapoptotic dead cells were found in the tail of the Apaf-1 À/À embryos, suggesting that the Apaf-1-independent programmed cell death occurred, and these dead cells were engulfed by macrophages. In contrast, active caspase-3 was detected in E14.5 thymus of Apaf-1 À/À embryos. Treatment of fetal thymocytes with staurosporine, but not etoposide, induced processing of procaspases 3 and 9, indicating that the E14.5 thymocytes have the ability to undergo caspase-dependent apoptosis in an Apaf-1-independent manner. Thus, programmed cell death in mouse development, which normally proceeds in an efficient Apaf-1-depenent mechanism, appears to be backed up by Apaf-1-independent death systems.

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“…It has been shown by Kawane and colleagues that mice lacking the lysosomal endonuclease DNAse II (Dnase II -/-mice) are embryonically lethal, due to the impaired ability to degrade self-DNA by macrophages (Kawane et al, 2001). Genomic deletion of type I IFN Receptor (IFNAR) rescued Dnase II -/-mice from embryonic lethality (Yoshida et al, 2005), but the mice lacking both IFNAR and DNAse II (Dnase II -/-Ifnar -/-mice) would develop polyarthritis (Kawane et al, 2001). Interestingly, Baum and colleagues demonstrated a peculiar role for the AIM2 inflammasome in arthritis pathogenesis.…”

Section: Aim2 In Autoimmunity and Skin Diseasesmentioning

confidence: 99%

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

Canavese¹

2016

American Journal of Pharmacology and Toxicology

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Understanding the inflammasome biology is one of the most exciting challenges in immuno-pharmacology. The role of the inflammasomes has been recognized in the host defense mechanism against invading pathogens and in the development of several conditions, such as cancer, auto-inflammatory, autoimmune, metabolic and neurodegenerative disorders. DNA recognition by the cells is a crucial immunological step leading to the initiation of an innate immune response. Absent in Melanoma 2 (AIM2) is a cytoplasmic sensor that perceives double-stranded DNA of microbial or host origin. Once the DNA is bound, AIM2 assembles a multiprotein complex named inflammasome, which drives pyroptosis and proteolytic cleavage of pro-IL-1β and pro-IL-18 pro-inflammatory cytokines, leading to a protective inflammasome-mediated host response. However, improper recognition of self-DNA by AIM2 triggers deleterious inflammatory responses, leading to systemic inflammation and several pathological conditions. Therefore, understanding the mechanisms of AIM2-inflammasome-mediated inflammation will provide an essential knowledge base to develop new successful therapeutic strategies to cure the outlined pathologies in which AIM2-inflammasome activation plays a key role, as well as to guide clinical practice. This mini-review provides an overview on the latest research findings on AIM2 inflammasome, with particular focus on its role in autoimmunity and skin disorders. An update on its therapeutic implications has also been documented.

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Requirement of DNase II for Definitive Erythropoiesis in the Mouse Fetal Liver

Cited by 345 publications

References 25 publications

DNase II deficiency impairs innate immune function in Drosophila

DNase II deficiency impairs innate immune function in Drosophila

Apaf-1-independent programmed cell death in mouse development

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

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