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Modulation of inflammation by autophagy: Consequences for human disease

View Article: PubMed Central - PubMed

ABSTRACT

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.

No MeSH data available.


The process of autophagy in eukaryotic cells and its involvement in cellular homeostasis, metabolism, and the immune system. Autophagy is induced both by metabolic and immune signals comprising pathogen recognition and stimulation by proinflammatory cytokines. Upon autophagy triggering through any of these pathways, the MAP1LC3B (depicted as unconjugated LC3B-I and PE-conjugated LC3B-II) and ATG12 conjugation systems, as well as BECN1 and class III PtdIns3K, are activated that are critical for autophagosome formation. After engulfment of the autophagic cargo, autophagosomes proceed to lysosomal fusion, leading to degradation of the sequestered content. In case the autophagic cargo originates from intracellular organelles or protein complexes, the degraded fragments are utilized for metabolic purposes to generate ATP and provide the cell with free amino acids. In contrast, autophagy-mediated degradation of extracellular material, especially microbes, enables pathogen killing and activation of adaptive immunity by MHC-dependent antigen presentation.
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f0001: The process of autophagy in eukaryotic cells and its involvement in cellular homeostasis, metabolism, and the immune system. Autophagy is induced both by metabolic and immune signals comprising pathogen recognition and stimulation by proinflammatory cytokines. Upon autophagy triggering through any of these pathways, the MAP1LC3B (depicted as unconjugated LC3B-I and PE-conjugated LC3B-II) and ATG12 conjugation systems, as well as BECN1 and class III PtdIns3K, are activated that are critical for autophagosome formation. After engulfment of the autophagic cargo, autophagosomes proceed to lysosomal fusion, leading to degradation of the sequestered content. In case the autophagic cargo originates from intracellular organelles or protein complexes, the degraded fragments are utilized for metabolic purposes to generate ATP and provide the cell with free amino acids. In contrast, autophagy-mediated degradation of extracellular material, especially microbes, enables pathogen killing and activation of adaptive immunity by MHC-dependent antigen presentation.

Mentions: Several types of autophagy have been recognized, including macroautophagy, microautophagy, chaperone-mediated autophagy, and noncanonical autophagy.5 In this review we will focus on macroautophagy, which will be henceforth referred to as autophagy. This process is activated in response to a multitude of stress factors including starvation, hypoxia, and other toxins that result in accumulation of damaged organelles and protein aggregates. As a consequence, a double-layer membrane, the phagophore, is formed to engulf the damaged cytosolic components (Fig. 1). After complete sequestration of these components, the resulting autophagosome fuses with the lysosome, which enables the breakdown of the autophagosome inner membrane and exposes the cargo to the lysosomal hydrolases. The resulting breakdown products are subsequently released in the cytosol and are available to be reused for the synthesis of required macromolecules.5 Several autophagy-related (ATG) genes and proteins are involved in the induction of autophagy (Fig. 1), while a subset of them also have autophagy-independent functions.6Figure 1.


Modulation of inflammation by autophagy: Consequences for human disease
The process of autophagy in eukaryotic cells and its involvement in cellular homeostasis, metabolism, and the immune system. Autophagy is induced both by metabolic and immune signals comprising pathogen recognition and stimulation by proinflammatory cytokines. Upon autophagy triggering through any of these pathways, the MAP1LC3B (depicted as unconjugated LC3B-I and PE-conjugated LC3B-II) and ATG12 conjugation systems, as well as BECN1 and class III PtdIns3K, are activated that are critical for autophagosome formation. After engulfment of the autophagic cargo, autophagosomes proceed to lysosomal fusion, leading to degradation of the sequestered content. In case the autophagic cargo originates from intracellular organelles or protein complexes, the degraded fragments are utilized for metabolic purposes to generate ATP and provide the cell with free amino acids. In contrast, autophagy-mediated degradation of extracellular material, especially microbes, enables pathogen killing and activation of adaptive immunity by MHC-dependent antigen presentation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836004&req=5

f0001: The process of autophagy in eukaryotic cells and its involvement in cellular homeostasis, metabolism, and the immune system. Autophagy is induced both by metabolic and immune signals comprising pathogen recognition and stimulation by proinflammatory cytokines. Upon autophagy triggering through any of these pathways, the MAP1LC3B (depicted as unconjugated LC3B-I and PE-conjugated LC3B-II) and ATG12 conjugation systems, as well as BECN1 and class III PtdIns3K, are activated that are critical for autophagosome formation. After engulfment of the autophagic cargo, autophagosomes proceed to lysosomal fusion, leading to degradation of the sequestered content. In case the autophagic cargo originates from intracellular organelles or protein complexes, the degraded fragments are utilized for metabolic purposes to generate ATP and provide the cell with free amino acids. In contrast, autophagy-mediated degradation of extracellular material, especially microbes, enables pathogen killing and activation of adaptive immunity by MHC-dependent antigen presentation.
Mentions: Several types of autophagy have been recognized, including macroautophagy, microautophagy, chaperone-mediated autophagy, and noncanonical autophagy.5 In this review we will focus on macroautophagy, which will be henceforth referred to as autophagy. This process is activated in response to a multitude of stress factors including starvation, hypoxia, and other toxins that result in accumulation of damaged organelles and protein aggregates. As a consequence, a double-layer membrane, the phagophore, is formed to engulf the damaged cytosolic components (Fig. 1). After complete sequestration of these components, the resulting autophagosome fuses with the lysosome, which enables the breakdown of the autophagosome inner membrane and exposes the cargo to the lysosomal hydrolases. The resulting breakdown products are subsequently released in the cytosol and are available to be reused for the synthesis of required macromolecules.5 Several autophagy-related (ATG) genes and proteins are involved in the induction of autophagy (Fig. 1), while a subset of them also have autophagy-independent functions.6Figure 1.

View Article: PubMed Central - PubMed

ABSTRACT

Autophagy and inflammation are 2 fundamental biological processes involved in both physiological and pathological conditions. Through its crucial role in maintaining cellular homeostasis, autophagy is involved in modulation of cell metabolism, cell survival, and host defense. Defective autophagy is associated with pathological conditions such as cancer, autoimmune disease, neurodegenerative disease, and senescence. Inflammation represents a crucial line of defense against microorganisms and other pathogens, and there is increasing evidence that autophagy has important effects on the induction and modulation of the inflammatory reaction; understanding the balance between these 2 processes may point to important possibilities for therapeutic targeting. This review focuses on the crosstalk between autophagy and inflammation as an emerging field with major implications for understanding the host defense on the one hand, and for the pathogenesis and treatment of immune-mediated diseases on the other hand.

No MeSH data available.