Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis

Jonsson, Helena; Allen, Paul M.; Peng, Stanford L.

doi:10.1038/nm1248

Cited by 193 publications

(190 citation statements)

References 29 publications

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“…18 In line with the prolonged life span of neutrophils in the absence of endogenous IFN-b, decreased expression of Fas on neutrophils derived from tumors ( (Fig. 2a).…”

Section: Decreased Fas Expression On Neutrophils From Tumor Bearing Isupporting

confidence: 62%

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Andzinski

Lienenklaus

et al. 2014

Intl Journal of Cancer

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The importance of neutrophils in tumor immune surveillance, invasive growth and angiogenesis becomes increasingly clear. Many of neutrophil activities are controlled by endogenous IFN-b. Here, we provide evidence that endogenous IFN-b is regulating the apoptosis of pro-angiogenic tumor infiltrating neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Accordingly, the life span of tumor associated neutrophils (TANs) is remarkably prolonged in tumor bearing Ifnb1 2/2 mice compared to wild type controls. Lower expression of Fas, reactive oxygen species, active Caspase 3 and 9, as well as a change in expression pattern of proapoptotic and antiapoptotic members of the Bcl-2 family and the major apoptosome constituent Apaf-1 is observed under such conditions. In line with inhibition of apoptosis and the prolonged neutrophil survival, in the absence of endogenous IFN-b, a strong enhancement of G-CSF expression and PI3 Kinase phosphorylation is detected. These data explain the increased longevity of tumor infiltrating neutrophils and the accumulation of such cells in tumors. Taken together, our findings add to the important role of Type I IFN in immune surveillance against cancer.Neutrophilic granulocytes are the most abundant white blood cells in circulation, that are released from the bone marrow as terminally differentiated, nondividing cells. 1 Besides their role in immunity, neutrophils strongly influence growth, metastasis, 2 angiogenesis 3,4 and immune surveillance 5 of tumors. In contrast to cells of the adaptive immune system, neutrophils need no activation to acquire an effector phenotype. In accordance with their pleiotropic function, neutrophils are equipped with a large array of effector molecules like proteolytic enzymes, antimicrobial proteins/peptides and are able to produce reactive oxygen species. 6 Due to their potential toxicity against host tissue, the life span of such cells is strictly regulated. 7 In the absence of noxious or inflammatory stimuli, neutrophils are removed from circulation by apoptosis shortly after their emigration from the bone marrow. However, several proinflammatory cytokines have been shown to influence the longevity of neutrophils. 8 Type I interferons (IFNs) were first identified as factors responsible for the phenomenon of viral interference. In the meantime, they are recognized to influence a broad variety of biological processes, such as maintenance of cellular homeostasis, 9 hematopoiesis, 10 lymphocyte development 11 and apoptosis of dendritic 12 or CD4 1 T cells 13 besides their role in infections. In addition, Type I IFNs display strong antitumor effects by exhibiting direct antiproliferative and proapoptotic effects on tumor cells 14 as well as supporting systemic immunity against tumor targets by up-regulation of MHC class I expression, enhancement of cytotoxic T cell responses and activation of natural killer cells and macrophages. 15 Nevertheless, the mechanism of how Type I IFNs contribute to immune surveillance against tumo...

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“…18 In line with the prolonged life span of neutrophils in the absence of endogenous IFN-b, decreased expression of Fas on neutrophils derived from tumors ( (Fig. 2a).…”

Section: Decreased Fas Expression On Neutrophils From Tumor Bearing Isupporting

confidence: 62%

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Andzinski

Lienenklaus

et al. 2014

Intl Journal of Cancer

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“…Our work demonstrated that miR-484 regulates Fis1 through targeting the amino acid coding sequence. Noticeably, Foxo3a can inhibit apoptosis 19,44 . In consistence with the anti-apoptotic function of Foxo3a, we identified that Foxo3a can transactivate miR-484 expression.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, there are also reports showing that it can inhibit apoptosis 19,44 . It stimulates the expression of the anti-apoptotic factors including manganese superoxide dismutase 48 and catalase 49 .…”

Section: Discussionmentioning

confidence: 99%

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miR-484 regulates mitochondrial network through targeting Fis1

et al. 2012

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mitochondria constantly undergo fusion and fission, two necessary processes for the maintenance of organelle fidelity. The abnormal mitochondrial fission participates in the pathogenesis of many diseases, but its regulation remains poorly understood. Here we show that miR-484 can suppress translation of mitochondrial fission protein Fis1, and inhibit Fis1-mediated fission and apoptosis in cardiomyocytes and in the adrenocortical cancer cells. We demonstrate that Fis1 is necessary for mitochondrial fission and apoptosis, and is upregulated during anoxia, whereas miR-484 is downregulated. miR-484 is able to attenuate Fis1 upregulation and mitochondrial fission, by binding to the amino acid coding sequence of Fis1 and inhibiting its translation. In exploring the underlying mechanism of miR-484 downregulation upon apoptosis, we observe that Foxo3a transactivates miR-484 expression. Foxo3a transgenic or knockout mice exhibit, respectively, a high or low level of miR-484 and a reduced or enhanced mitochondrial fission, apoptosis and myocardial infarction. our data reveal a model of mitochondrial fission regulation by a microRnA.

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“…DNA samples recovered from DNA-Protein immunocomplexes were amplified by PCR using the following primer sets: 38 …”

Section: Chip Assaymentioning

confidence: 99%

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

et al. 2006

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Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5-or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5À/À and mek5À/À fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.

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Inflammatory arthritis requires Foxo3a to prevent Fas ligand–induced neutrophil apoptosis

Cited by 193 publications

References 29 publications

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

Delayed apoptosis of tumor associated neutrophils in the absence of endogenous IFN‐β

miR-484 regulates mitochondrial network through targeting Fis1

Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

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