The Goldilocks Conundrum: NLR Inflammasome Modulation of Gastrointestinal Inflammation during Inflammatory Bowel Disease

Abstract

Recent advances have revealed significant insight into Inflammatory bowel disease (IBD) pathobiology. Ulcerative colitis and Crohn's disease, the chronic relapsing clinical manifestations of IBD, are complex disorders with genetic and environmental influences. These diseases are associated with the dysregulation of immune tolerance, excessive Inflammation, and damage to the epithelial cell barrier. Increasing evidence indicates that pattern recognition receptors, including Toll-like receptors (TLRs) and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs), function to maintain immune system homeostasis, modulate the gastrointestinal microbiome, and promote proper intestinal epithelial cell regeneration and repair. New insights have revealed that NLR family members are essential components in maintaining this immune system homeostasis. To date, the vast majority of studies associated with NLRs have focused on family members that form a multiprotein signaling platform called the Inflammasome. These signaling complexes are responsible for the cleavage and activation of the potent pleotropic cytokines IL-1β and IL-18, and they facilitate a unique form of cell death defined as pyroptosis. In this review, we summarize the current paradigms associated with NLR Inflammasome maintenance of immune system homeostasis in the gastrointestinal system. New concepts related to canonical and noncanonical Inflammasome signaling, as well as the implications of classical and alternative Inflammasomes in IBD pathogenesis, are also reviewed.

Maternal Influence and Murine Housing Confound Impact of NLRP1 Inflammasome on Microbiome Composition

“…Due to its role as a pan-inflammasome adaptor protein, the role of ASC in IBD and colitis-associated cancer has been well studied. In models based on chemically induced colitis, loss of ASC results in a highly severe phenotype compared to other individual NLR-deficient genotypes [reviewed in 8]. The consensus data agree that mice lacking functional ASC fail to generate mature IL-1β and IL-18 in the colon during models of experimental colitis, which results in immune system and epithelial barrier defects [11].…”

“…In the GI tract, NLR family members are essential mediators of inflammation during IBD and maintain immune system homeostasis [8]. There are 22 distinct NLR and NLR-like proteins identified in humans and several murine paralogs, many of which have yet to be fully characterized.…”

“…In general, the majority of studies evaluating NLR inflammasomes have found that loss of any specific NLR or inflammasome component results in increased GI inflammation, epithelial cell barrier disruption, and inflammation-driven tumorigenesis. Inflammasome formation has been suggested to maintain immune system homeostasis in the gut and attenuate IBD progression through a variety of mechanisms, including promoting epithelial cell regeneration and repair, facilitating T-cell differentiation, and controlling cell death [8, 17]. This evidence has strongly suggested that a function of NLR family members in the gut is likely associated with their recognition of pathogenic and commensal members of the host microbiome and their modulation of a balanced host immune response following loss of epithelial cell barrier integrity [18, 19].…”

“…Notably, we also saw evidence of increased expression of NLRP1 in human subjects with active ulcerative colitis relative to healthy controls [9]. Beyond IBD, polymorphisms in the NLRP1 gene have been associated with several autoimmune disorders, including vitiligo, celiac disease, rheumatoid arthritis, systemic lupus erythematosus, and type I diabetes [8]. It is clear that NLRP1 plays an important role in modulating inflammatory diseases, but the direct mechanism/s has not yet been defined.…”

Ag-NP-induced interleukin-1beta upregulation in a lung co-culture model

“…So far, four inflammasomes have been identified, containing an inflammasome sensor, the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC-CARD), and pro-caspase-1. Inflammasome activation is crucial for host defense against pathogens but excessive or prolonged-activation, or loss of function, has been linked to autoinflammatory disorders, so a better understanding of toxicity associated with inflammasome activation is imperative for the prevention of autoimmune disorders, such as chronic asthma, inflammatory bowel disease (IBD), and many others [1][2][3][4][5].…”