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Modulation of inflammation by autophagy: Consequences for human disease

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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.

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Interplay between autophagy and inflammation in the pathogenesis of Crohn disease. Multiple facets of inflammatory pathways involved in CD pathogenesis are influenced by autophagy, ranging on the one hand from defective microbial recognition and phagocytosis in dendritic cells (DCs) through the PRR NOD2, diminished antigen processing and presentation on MHC class I/II caused by genetic variants in ATG16L1, IRGM, and CALCOCO2, and on the other hand to a loss of inhibition of IL1B and IL18 production, important pro-inflammatory mediators leading to generation of Th1 and Th17 responses. Furthermore, genetic variation in ATG16L1 impairs the capacity of Paneth cells to excrete antimicrobial peptides, including DEFA/α- and DEFB/β-defensins. All together, these defects allow for microbial overgrowth and lead to hyperinflammation. DC, dendritic cell; TCR, T cell receptor.
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f0003: Interplay between autophagy and inflammation in the pathogenesis of Crohn disease. Multiple facets of inflammatory pathways involved in CD pathogenesis are influenced by autophagy, ranging on the one hand from defective microbial recognition and phagocytosis in dendritic cells (DCs) through the PRR NOD2, diminished antigen processing and presentation on MHC class I/II caused by genetic variants in ATG16L1, IRGM, and CALCOCO2, and on the other hand to a loss of inhibition of IL1B and IL18 production, important pro-inflammatory mediators leading to generation of Th1 and Th17 responses. Furthermore, genetic variation in ATG16L1 impairs the capacity of Paneth cells to excrete antimicrobial peptides, including DEFA/α- and DEFB/β-defensins. All together, these defects allow for microbial overgrowth and lead to hyperinflammation. DC, dendritic cell; TCR, T cell receptor.

Mentions: The first major autoinflammatory disease in which autophagy has been suggested to play a significant role is Crohn disease (CD). CD is a chronic inflammatory disorder of the intestine caused by a combination of multiple factors including defective host response, altered mucosal barrier function, and exaggerated cytokine production. Genetic variants of important autophagy genes such as ATG16L1, IRGM, and ULK1, have been reproducibly associated with susceptibility and clinical outcome of the disease, demonstrating the important role of autophagy in CD.48-51 Functional studies have revealed that autophagy and subsequently inflammatory pathways are heavily influenced by genetic variation in autophagy genes, the ATG16L1 variant in particular, as has been demonstrated for defective Paneth cell function,52 impaired bacterial defense,53,54 aberrant antigen presentation,55,56 and increased production of proinflammatory cytokines including IL1B and IL18.57-59 The IRGM promoter polymorphism risk allele influences IRGM expression, at least in part through posttranscriptional regulation by miRNAs.60,61 Furthermore, a well-established genetic risk factor with the highest predictive value for CD is for the gene encoding NOD2, a PRR that recognizes peptidoglycans and activates immune pathways and autophagy.62-65 Another indication that autophagy is a central process in intestinal homeostasis is the recent finding of CALCOCO2/NDP52 mutations in CD patients, a gene that codes for an important factor in phagophore targeting of intracellular bacteria (Fig. 3).66,67Figure 3.


Modulation of inflammation by autophagy: Consequences for human disease
Interplay between autophagy and inflammation in the pathogenesis of Crohn disease. Multiple facets of inflammatory pathways involved in CD pathogenesis are influenced by autophagy, ranging on the one hand from defective microbial recognition and phagocytosis in dendritic cells (DCs) through the PRR NOD2, diminished antigen processing and presentation on MHC class I/II caused by genetic variants in ATG16L1, IRGM, and CALCOCO2, and on the other hand to a loss of inhibition of IL1B and IL18 production, important pro-inflammatory mediators leading to generation of Th1 and Th17 responses. Furthermore, genetic variation in ATG16L1 impairs the capacity of Paneth cells to excrete antimicrobial peptides, including DEFA/α- and DEFB/β-defensins. All together, these defects allow for microbial overgrowth and lead to hyperinflammation. DC, dendritic cell; TCR, T cell receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0003: Interplay between autophagy and inflammation in the pathogenesis of Crohn disease. Multiple facets of inflammatory pathways involved in CD pathogenesis are influenced by autophagy, ranging on the one hand from defective microbial recognition and phagocytosis in dendritic cells (DCs) through the PRR NOD2, diminished antigen processing and presentation on MHC class I/II caused by genetic variants in ATG16L1, IRGM, and CALCOCO2, and on the other hand to a loss of inhibition of IL1B and IL18 production, important pro-inflammatory mediators leading to generation of Th1 and Th17 responses. Furthermore, genetic variation in ATG16L1 impairs the capacity of Paneth cells to excrete antimicrobial peptides, including DEFA/α- and DEFB/β-defensins. All together, these defects allow for microbial overgrowth and lead to hyperinflammation. DC, dendritic cell; TCR, T cell receptor.
Mentions: The first major autoinflammatory disease in which autophagy has been suggested to play a significant role is Crohn disease (CD). CD is a chronic inflammatory disorder of the intestine caused by a combination of multiple factors including defective host response, altered mucosal barrier function, and exaggerated cytokine production. Genetic variants of important autophagy genes such as ATG16L1, IRGM, and ULK1, have been reproducibly associated with susceptibility and clinical outcome of the disease, demonstrating the important role of autophagy in CD.48-51 Functional studies have revealed that autophagy and subsequently inflammatory pathways are heavily influenced by genetic variation in autophagy genes, the ATG16L1 variant in particular, as has been demonstrated for defective Paneth cell function,52 impaired bacterial defense,53,54 aberrant antigen presentation,55,56 and increased production of proinflammatory cytokines including IL1B and IL18.57-59 The IRGM promoter polymorphism risk allele influences IRGM expression, at least in part through posttranscriptional regulation by miRNAs.60,61 Furthermore, a well-established genetic risk factor with the highest predictive value for CD is for the gene encoding NOD2, a PRR that recognizes peptidoglycans and activates immune pathways and autophagy.62-65 Another indication that autophagy is a central process in intestinal homeostasis is the recent finding of CALCOCO2/NDP52 mutations in CD patients, a gene that codes for an important factor in phagophore targeting of intracellular bacteria (Fig. 3).66,67Figure 3.

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.


Related in: MedlinePlus