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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 interplay between autophagy and IL1B-inflammasome activation. Production of the pro-inflammatory cytokines IL1B and IL18 is pivotal in antimicrobial host defense, since this leads to activation of both innate and adaptive immune responses including Th1 and Th17. Autophagy potently regulates these immune responses by several means. First, autophagy inhibits IL1B and IL18 production through digestion of dysfunctional mitochondria and thereby prevention of mitochondrial ROS release that is known to activate the inflammasome. Second, autophagy is capable of targeting inflammasome complexes for degradation, which prevents cleavage of pro-IL1B and pro-IL18 into their biologically active counterparts. Finally, the autophagy machinery engulfs and eradicates pro-IL1B proteins, representing another level of IL1B regulation. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; ROS, reactive oxygen species.
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f0002: The interplay between autophagy and IL1B-inflammasome activation. Production of the pro-inflammatory cytokines IL1B and IL18 is pivotal in antimicrobial host defense, since this leads to activation of both innate and adaptive immune responses including Th1 and Th17. Autophagy potently regulates these immune responses by several means. First, autophagy inhibits IL1B and IL18 production through digestion of dysfunctional mitochondria and thereby prevention of mitochondrial ROS release that is known to activate the inflammasome. Second, autophagy is capable of targeting inflammasome complexes for degradation, which prevents cleavage of pro-IL1B and pro-IL18 into their biologically active counterparts. Finally, the autophagy machinery engulfs and eradicates pro-IL1B proteins, representing another level of IL1B regulation. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; ROS, reactive oxygen species.

Mentions: Production of cytokines from the IL1 family, and especially IL1B, is one of the main mechanisms through which innate and adaptive immune responses are induced by an infection. The regulation of the production of this cytokine is thus crucial for understanding inflammation and host defense. Probably the best studied aspect of the interaction between autophagy and inflammation is represented by the effects of autophagy on inflammasome activation and IL1B release. An overview of the interplay between autophagy and IL1B-inflammasome activation is depicted in Figure 2. The inflammasome consists of protein complexes formed by one or more members of the NLR family of receptors together with CASP1/caspase-1, leading to the activation of this cysteine protease, and processing of the inactive pro-IL1B and pro-IL18 into active cytokines.31 The first observation regarding the effect of autophagy on inflammasome activation was that of Saitoh et al. who reported that macrophages of Atg16l1 knockout mice respond with increased production of IL1B after stimulation with LPS. This was due to an exaggerated activation of CASP1 in the Atg16l1-deficient mice, mediated by the adapter molecule TICAM.32 Additional studies support the concept that autophagy regulates inflammasome activation.33-36Figure 2.


Modulation of inflammation by autophagy: Consequences for human disease
The interplay between autophagy and IL1B-inflammasome activation. Production of the pro-inflammatory cytokines IL1B and IL18 is pivotal in antimicrobial host defense, since this leads to activation of both innate and adaptive immune responses including Th1 and Th17. Autophagy potently regulates these immune responses by several means. First, autophagy inhibits IL1B and IL18 production through digestion of dysfunctional mitochondria and thereby prevention of mitochondrial ROS release that is known to activate the inflammasome. Second, autophagy is capable of targeting inflammasome complexes for degradation, which prevents cleavage of pro-IL1B and pro-IL18 into their biologically active counterparts. Finally, the autophagy machinery engulfs and eradicates pro-IL1B proteins, representing another level of IL1B regulation. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; ROS, reactive oxygen species.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836004&req=5

f0002: The interplay between autophagy and IL1B-inflammasome activation. Production of the pro-inflammatory cytokines IL1B and IL18 is pivotal in antimicrobial host defense, since this leads to activation of both innate and adaptive immune responses including Th1 and Th17. Autophagy potently regulates these immune responses by several means. First, autophagy inhibits IL1B and IL18 production through digestion of dysfunctional mitochondria and thereby prevention of mitochondrial ROS release that is known to activate the inflammasome. Second, autophagy is capable of targeting inflammasome complexes for degradation, which prevents cleavage of pro-IL1B and pro-IL18 into their biologically active counterparts. Finally, the autophagy machinery engulfs and eradicates pro-IL1B proteins, representing another level of IL1B regulation. DAMP, danger-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; ROS, reactive oxygen species.
Mentions: Production of cytokines from the IL1 family, and especially IL1B, is one of the main mechanisms through which innate and adaptive immune responses are induced by an infection. The regulation of the production of this cytokine is thus crucial for understanding inflammation and host defense. Probably the best studied aspect of the interaction between autophagy and inflammation is represented by the effects of autophagy on inflammasome activation and IL1B release. An overview of the interplay between autophagy and IL1B-inflammasome activation is depicted in Figure 2. The inflammasome consists of protein complexes formed by one or more members of the NLR family of receptors together with CASP1/caspase-1, leading to the activation of this cysteine protease, and processing of the inactive pro-IL1B and pro-IL18 into active cytokines.31 The first observation regarding the effect of autophagy on inflammasome activation was that of Saitoh et al. who reported that macrophages of Atg16l1 knockout mice respond with increased production of IL1B after stimulation with LPS. This was due to an exaggerated activation of CASP1 in the Atg16l1-deficient mice, mediated by the adapter molecule TICAM.32 Additional studies support the concept that autophagy regulates inflammasome activation.33-36Figure 2.

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.