Autophagy genes in immunity. Nat Immunol

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nature Immunology (Impact Factor: 20). 06/2009; 10(5):461-70. DOI: 10.1038/ni.1726
Source: PubMed


In its classical form, autophagy is a pathway by which cytoplasmic constituents, including intracellular pathogens, are sequestered in a double-membrane-bound autophagosome and delivered to the lysosome for degradation. This pathway has been linked to diverse aspects of innate and adaptive immunity, including pathogen resistance, production of type I interferon, antigen presentation, tolerance and lymphocyte development, as well as the negative regulation of cytokine signaling and inflammation. Most of these links have emerged from studies in which genes encoding molecules involved in autophagy are inactivated in immune effector cells. However, it is not yet known whether all of the critical functions of such genes in immunity represent 'classical autophagy' or possible as-yet-undefined autophagolysosome-independent functions of these genes. This review summarizes phenotypes that result from the inactivation of autophagy genes in the immune system and discusses the pleiotropic functions of autophagy genes in immunity.

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    • "A role for nuclear factor (NF)-κB has previously been suggested in SM-induced apoptosis in human keratinocytes, and it may play a similar role in lung epithelial cells (Ruff and Dillman, 2010). Transmission electron microscopy of lung sections has also revealed the presence of autophagosomes (Malaviya et al., 2010) which correlates with increased expression of LC3B-II, a lipidated form of LC3B-I protein known to associate with autophagosomal membranes (Virgin and Levine, 2009). "
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    ABSTRACT: Exposure of humans and animals to vesicants, including sulfur mustard (SM) and nitrogen mustard (NM), causes severe and debilitating damage to the respiratory tract. Both acute and long term pathological consequences are observed in the lung following a single exposure to these vesicants. Evidence from our laboratories and others suggest that macrophages and inflammatory mediators they release play an important role in mustard-induced lung injury. In this paper, the pathogenic effects of SM and NM on the lung are reviewed, along with the potential role of inflammatory macrophages and mediators they release in mustard-induced pulmonary toxicity.
    Toxicology Letters 10/2015; DOI:10.1016/j.toxlet.2015.10.011 · 3.26 Impact Factor
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    • "Our recent study demonstrated a suppressed autophagic response in the skeletal muscle of young G93A mice before disease onset (Xiao et al. 2015). In the intestine, we specifically noticed a decrease in normal Paneth cells and a reduction in lysozyme 1, one of the proteases in lysosomes associated with autophagy maturation (Phan et al. 2009; Virgin and Levine 2009). Decreased levels of the antimicrobial peptide defensin were also found in the G93A intestine. "
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    ABSTRACT: Emerging evidence has demonstrated that intestinal homeostasis and the microbiome play essential roles in neurological diseases, such as Parkinson's disease. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and muscle atrophy. Currently, there is no effective treatment. Most patients die within 3–5 years due to respiratory paralysis. Although the death of motor neurons is a hallmark of ALS, other organs may also contribute to the disease progression. We examined the gut of an ALS mouse model, G93A, which expresses mutant superoxide dismutase (SOD1G93A), and discovered a damaged tight junction structure and increased permeability with a significant reduction in the expression levels of tight junction protein ZO-1 and the adherens junction protein E-cadherin. Furthermore, our data demonstrated increased numbers of abnormal Paneth cells in the intestine of G93A mice. Paneth cells are specialized intestinal epithelial cells that can sense microbes and secrete antimicrobial peptides, thus playing key roles in host innate immune responses and shaping the gut microbiome. A decreased level of the antimicrobial peptides defensin 5 alpha was indeed found in the ALS intestine. These changes were associated with a shifted profile of the intestinal microbiome, including reduced levels of Butyrivibrio Fibrisolvens, Escherichia coli, and Fermicus, in G93A mice. The relative abundance of bacteria was shifted in G93A mice compared to wild-type mice. Principal coordinate analysis indicated a difference in fecal microbial communities between ALS and wild-type mice. Taken together, our study suggests a potential novel role of the intestinal epithelium and microbiome in the progression of ALS.
    04/2015; 3(4). DOI:10.14814/phy2.12356
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    • "Autophagy is involved in the development and/or homeostasis of several immune cell populations [32]. Indeed the knockout of different autophagy genes in specific lymphocyte populations in mice has shown a crucial role for autophagy proteins in the development and maintenance of normal numbers of B cells, CD4+ T cells, CD8+ T cells, in antigen presentation and in the elimination of autoreactive T cells in the thymus [19–25]. Moreover, both autophagy and leptin have been suggested to play a key role in the modulation of the onset and outcome of several autoimmune diseases [33]. "
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    ABSTRACT: Objective In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4+CD25− conventional (Tconv) T cells. Results In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy. Materials/Methods The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays. Conclusions Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
    Metabolism 10/2014; 63(10). DOI:10.1016/j.metabol.2014.06.010 · 3.89 Impact Factor
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