Abstract
Pattern recognition receptors such as nucleotide-binding oligomerization domain (NOD)-containing protein receptors (NLRs) and the pyrin and hematopoitic interferon-inducible nuclear protein (HIN) domain (PYHIN) receptors initiate the inflammatory response following cell stress or pathogenic challenge. When activated, some of these receptors oligomerize to form the structural backbone of a signalling platform known as an inflammasome. Inflammasomes promote the activation of caspase-1 and the maturation of the proinflammatory cytokines, interleukin (IL)-1β and IL-18. The gut dysregulation of the inflammasome complex is thought to be a contributing factor in the development of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD). The importance of inflammasomes to intestinal health has been emphasized by various inflammasome-deficient mice in dextran sulphate sodium (DSS) models of intestinal inflammation and by the identification of novel potential candidate genes in population-based human studies. In this review, we summarise the most recent findings with regard to the formation, sensing, and regulation of the inflammasome complex and highlight their importance in maintaining intestinal health.
Highlights
The gastrointestinal environment is a continuous system with a dual function
Formation of a NOD-Like Receptor Protein (NLRP) inflammasome is initiated by ligand activation of the receptor protein and this causes the NLR proteins to oligomerize through their nucleotide-binding and oligomerization (NACHT) domains (Figure 2)
In human U937 monocyte-derived macrophages, NLRC4 activation does not occur in response to flagellin or T3SS rod protein but occurs in response to the T3SS subunit Cprl from Chromobacterium violaceum, which raises the possibility that other accessory proteins may be involved in activation of the human NLRC4 inflammasome [69]
Summary
The gastrointestinal environment is a continuous system with a dual function. Firstly, it provides the human body with the energy it needs to grow and develop and aids in the elimination of waste material. Caspase-11-induced pyroptosis is thought to occur upstream of canonical inflammasomes in response to lipopolysaccharides (LPS) sensed in Gram-negative bacteria Both mechanisms are considered important for microbial defences in the gut [12,13]. The NLRP inflammasome complex consists of a nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) protein, a caspase and often an adaptor protein known as apoptosis-associated, speck-like protein containing a CARD (ASC) [2,14]. Formation of a NLRP inflammasome is initiated by ligand activation of the receptor protein and this causes the NLR proteins to oligomerize through their nucleotide-binding and oligomerization (NACHT) domains (Figure 2) This oligomerization creates a platform of NLRPYD molecules at the N-terminal and, through NLRPYD/ASCPYD interactions, nucleates helical ASC clusters to form an ASC filament structure. SSttrruuccttuurree ooff tthhee hhuummaann ppyyrriinn aanndd hheemmaattooppooiittiicc iinntteerrffeerroonn--iinndduucciibbllee nnuucclleeaarr pprrootteeiinn ((HHIINN)) ddoommaaiinn ((PPYYHHIINN)) ffaammiillyy. The absence of NOD2 prevents B. anthracis-induced IL-1β secretion but has little effect on the transcription of proIL-1β, indicating the importance of the NOD2-NLRP1 association in host defences against B. anthracis [34]
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