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Autophagosomes and subsequent bacteria degradation [47]. Polymorphisms in ATG16L1 and NOD2 genes have been linked to Crohn’s disease, an intestinal inflammatory disease. Cells obtained from Crohn’s disease patients with the ATG16L1 (T300A) polymorphism have decreased autophagic activity following exposure to muramyl dipeptides. In addition, a truncated version of NOD2 found in some patients with Crohn’s disease cells leads to the retention of ATG16L1 in cytoplasm, inhibiting its recruitment to plasma membrane and reducing autophagic activity [48]. Inflammasomes are multimeric protein complexes that activate caspase-1. They are assembled following the detection of a variety of cytosolic threats including infection, tissue damage, and metabolic abnormalities [491]. They consist of a sensor molecule (a NLR protein), an adaptor molecule ASC, and caspase-1 [52]. Most NLR proteins haveScientifica an amino-terminal caspase-recruitment-and-activation domain (CARD) or a pyrin domain; a Nod (or NACHT domain) that mediates self-oligomerization; and carboxyterminal leucine-rich repeats (LRRs), which sense specific stimuli. Following their activation, NLRs oligomerize via their NACHT domains and connect to caspase-1 via the adaptor protein ASC, which consists of a pyrin domain and a CARD domain [53]. ASC interacts with the upstream NLR sensor molecules via its pyrin domain. This interaction leads to the assembly of ASC dimers and oligomers that can sometimes be visualized as a large cytosolic speck [54]. The CARD domain of ASC recruits procaspase-1 monomers, which leads to the cleavage of the proform and the assembly of the active heterotetrameric caspase-1 [55]. Once activated, caspase-1 cleaves the proinflammatory cytokine precursors prointerleukin-1 (pro-IL-1) and pro-IL-18. This causes the production of the biologically active forms of IL-1 and IL-18, which are released from the cell by an unconventional secretory pathway [52]. 2.6. Autophagy and Inflammasomes. The association between Crohn’s disease and ATG16L1 polymorphisms ignited further investigations regarding the regulation of the inflammatory response by autophagic machinery [47].FX-11 To assess such a potential implication, Saitoh et al.Copanlisib generated an ATG16L1deficient mouse strain.PMID:23829314 This results in a failure to recruit the ATG12-ATG5 conjugate to isolation membranes and impairs the conjugation of LC3-I to phosphatidylethanolamine, leading to total absence of autophagosomes and a significant reduction in autophagy-dependent degradation [56]. To assess the consequences of defective autophagy, macrophages from wild type and ATG16L1-deficient mice were treated with LPS for 24 hours. Although TNF, IL-6, and IFN- production were unchanged, the level of IL-1 was markedly elevated. Furthermore, higher IL-1 levels were observed following the exposure of ATG16L1-deficient macrophages to ATP or to monosodium urate (MSU), known as NLRP3 inflammasome activators. Besides IL-1, elevations in IL-18 and active caspase-1 levels were observed in the ATG16L1 deficient macrophages. Similar results were found with ATG7-deficient macrophages. These studies indicate that impaired classical autophagy in macrophages elevates the production of inflammasome-specific cytokines, which suggested a regulatory action for the autophagic machinery on inflammasome activity [56]. Further studies focused on how autophagy regulated IL-1 secretion. Harris et al. found that pro-IL-1 is targeted by autophagosomes and degraded followin.