Article

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: 9.81). 11/2012; 109(46):E3168-E3176. DOI: 10.1073/pnas.1210500109
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
213 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy and phagocytosis are conserved cellular functions involved in innate immunity. However, the nature of their interactions remains unclear. We evaluated the role of autophagy in regulating phagocytosis in macrophages from myeloid-specific autophagy-related gene 7-deficient (Atg7(-/-)) mice. Atg7(-/-) macrophages exhibited higher bacterial uptake when infected with Mycobacterium tuberculosis (Mtb) or with M. tuberculosis var. bovis BCG (BCG). In addition, BCG-infected Atg7(-/-) mice showed increased bacterial loads and exacerbated lung inflammatory responses. Atg7(-/-) macrophages had increased expression of two class A scavenger receptors: macrophage receptor with collagenous structure (MARCO) and macrophage scavenger receptor 1 (MSR1). The increase in scavenger receptors was caused by increased activity of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) transcription factor resulting from accumulated sequestosome 1 (SQSTM1 or p62) in Atg7(-/-) macrophages. These insights increase our understanding of the host-pathogen relationship and suggest that therapeutic strategies should be designed to include modulation of both phagocytosis and autophagy.
    Immunity 09/2013; DOI:10.1016/j.immuni.2013.08.026 · 19.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy is an important intracellular homeostatic mechanism for the targeting of cytosolic constituents, including organelles, for lysosomal degradation. Autophagy plays roles in numerous physiological processes, including immune cell responses to endogenous and exogenous pathogenic stimuli. Moreover, autophagy has a potentially pivotal role to play in the regulation of inflammatory responses. In particular, autophagy regulates endogenous inflammasome activators, as well as inflammasome components and pro-IL-1beta. As a result, autophagy acts a key modulator of IL-1beta and IL-18, as well as IL-1alpha, release. This review focuses specifically on the role autophagy plays in regulating the production, processing, and secretion of IL-1 and IL-18 and the consequences of this important function.
    Frontiers in Immunology 04/2013; 4:83. DOI:10.3389/fimmu.2013.00083
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autophagy, an intracellular degradation process highly conserved from yeast to humans, is viewed as an important defence mechanism to clear intracellular bacteria. However, recent work has shown that autophagy may have different roles during different bacterial infections that restrict bacterial replication (anti-bacterial autophagy), act in cell autonomous signalling (non-bacterial autophagy) or support bacterial replication (pro-bacterial autophagy). This review will focus on newfound interactions of autophagy and pathogenic bacteria, highlighting that, in addition to delivering bacteria to the lysosome, autophagy responding to bacterial invasion may have a much broader role in mediating disease outcome.
    Cellular Microbiology 11/2012; 15(3). DOI:10.1111/cmi.12063 · 4.82 Impact Factor