Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation

Departments of Molecular Genetics and Microbiology and Internal Medicine and College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 11/2012; 109(46):E3168-E3176. DOI: 10.1073/pnas.1210500109
Source: PubMed


Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against
Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory.
M. tuberculosis infection of Atg5fl/fl LysM-Cre+ mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation
characterized by neutrophil infiltration and IL-17 response with increased IL-1α levels. Macrophages from uninfected Atg5fl/fl LysM-Cre+ mice displayed a cell-autonomous IL-1α hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization
during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing
both M. tuberculosis growth and damaging inflammation.

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    • "However, Mtb ensures its survival within host macrophages by arresting the maturation pathway that leads to phagosomeelysosome fusion, thus avoiding the phagolysosome that is rich in acid hydrolases capable of microbicidal degradation, and creating a suitable environment for bacillary survival and replication [6e8]. As yet, while Mtb can block phagosome maturation , the induction of autophagy facilitates phagosome-lysosome fusion and the bacilli clearance [9] [10]. "
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    ABSTRACT: Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response to be controlled. Macrophages play a central role in the response against Mycobacterium tuberculosis (Mtb). Given our prior studies in which adrenal steroids were found to modify the cellular immune responses from TB patients, it was sensible to analyze the immunomodulatory capability of cortisol and DHEA on macrophages infected with Mtb. The human macrophage-like THP-1 cells were infected with the H37Rv strain of Mtb and treated with Cortisol and DHEA at different doses. We monitored phagocytosis, intracellular-bacterial growth, autophagosoma formation, as well as cytokine gene expression and production. Cultures exposed to cortisol showed a decreased production of IL-1β, TNF-α, with DHEA being unable to modify the pattern of cytokine production or to reverse the cortisol inhibitory effects. Interestingly the intra-macrophagic bacterial burden was found reduced by DHEA treatment. While this effect was not related to a different cytokine pattern, in terms their production or mRNA expression, DHEA treatment did promote autophagy in Mtb-infected macrophages, irrespective of Cortisol presence. In essence, the better control of Mtb load by DHEA-treated macrophages seems to be dependent on an autophagic mechanism. The present results are relevant for two reasons as autophagy is not only important for clearance of mycobacteria but also for the prevention of tissue damage. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Tuberculosis 05/2015; 95(5). DOI:10.1016/ · 2.71 Impact Factor
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    • "several autoimmune disorders, particularly in Crohn's disease of which inflammation plays a key role in its pathogenesis (Hampe et al., 2007; Parkes et al., 2007; Rioux et al., 2007; Cadwell et al., 2008; Gianchecchi et al., 2013). Autophagy has also been shown to protect against bacterial infections, such as Mycobacterium tuberculosis, Burkholderia cenocepacia, and adherent-invasive Escherichia coli (Abdulrahman et al., 2011; Castillo et al., 2012; Chargui et al., 2012). Mechanistically, autophagy functions to clear damaged mitochondria to prevent the generation of reactive oxygen species and the release of mitochondrial DNA and thus suppresses the activation of inflammasomes and Toll-like receptor 9 (Nakahira et al., 2011; Oka et al., 2012). "
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    ABSTRACT: HBV and one of its encoded proteins, HBV X protein (HBx), have been shown to induce autophagy in hepatoma cells. Substantial evidence indicates that autophagy is a potent suppressor of inflammation. However, sporadic reports suggest that autophagy could promote pro-inflammatory cytokine expression and inflammation in some biological contexts. Here we show that overexpression of HBx induces LC3B-positive autophagosome formation, increases autophagic flux and enhances the expression of ATG5, ATG7, and LC3B-II in normal hepatocytes. Abrogation of autophagy by small interfering RNA against ATG5 and ATG7 prevents HBx-induced formation of autophagosomes. Autophagy inhibition also abrogates HBx-induced activation of nuclear factor-κB and production of interleukin-6 (IL-6), IL-8 and CXCL2. These findings suggest that autophagy is required for HBx-induced nuclear factor-κB activation and pro-inflammatory cytokine production and could shed new light on the complex role of autophagy in the modulation of inflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Cellular Physiology 02/2015; 230(10). DOI:10.1002/jcp.24967 · 3.84 Impact Factor
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    • "Thus, autophagy-deficient macrophages show excessive secretion of IL1α and IL1β, two cytokines that function together with IL-6 and TGF-β to promote Th17 differentiation and responses [42]; similarly, pharmacological inhibition of autophagy in dendritic cells enhances the production of inflammatory mediators from γδ T cells, including IL17 [43]. Concordantly, mice with selective deletion of autophagy protein in myeloid cells demonstrate enhanced inflammatory responses, including increased secretion/release of IL-1 and IL-17 in response to mycobacterium tuberculosis [42]. Given the reported profibrogenic role of IL-17 in the liver, whether macrophage and/or dentritic cell autophagy may also indirectly inhibit liver fibrosis via limitation of IL-17 release is an important issue that deserves further investigation. "
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    ABSTRACT: Liver fibrosis is a common wound healing response to chronic liver injury of all causes, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide. Fibrosis results from prolonged parenchymal cell apoptosis and necrosis associated with an inflammatory reaction that leads to recruitment of immune cells, activation and accumulation of fibrogenic cells, and extracellular matrix accumulation. The fibrogenic process is driven by hepatic myofibroblasts, that mainly derive from hepatic stellate cells undergoing a transdifferentiation from a quiescent, lipid-rich into a fibrogenic myofibroblastic phenotype, in response to paracrine/autocrine signals produced by neighbouring inflammatory and parenchymal cells. Autophagy is an important regulator of liver homeostasis under physiological and pathological conditions. This review focuses on recent findings showing that autophagy is a novel, but complex, regulatory pathway in liver fibrosis, with profibrogenic effects relying on its direct contribution to the process of hepatic stellate cell activation, but with antifibrogenic properties via indirect hepatoprotective and anti-inflammatory properties. Therefore, cell-specific delivery of drugs that exploit autophagic pathways is a prerequisite to further consider autophagy as a potential target for antifibrotic therapy.
    BioMed Research International 08/2014; 2014:869390. DOI:10.1155/2014/869390 · 2.71 Impact Factor
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