Modulation of inflammation by autophagy: Consequences for human disease
Romana T. Netea-Maier,a,b Theo S. Plantinga,a Frank L. van de Veerdonk,a,c Johannes W. Smit,a,b and Mihai G. Neteaa,c
The impact of autophagy on autoinflammatory and autoimmune diseases
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).66,67
Figure 3.
Figure 3.
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 ...
Romana T. Netea-Maier,a,b Theo S. Plantinga,a Frank L. van de Veerdonk,a,c Johannes W. Smit,a,b and Mihai G. Neteaa,c
The impact of autophagy on autoinflammatory and autoimmune diseases
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).66,67
Figure 3.
Figure 3.
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 ...