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Review
. 2011 Dec;141(6):1986-99.
doi: 10.1053/j.gastro.2011.10.002. Epub 2011 Oct 15.

Inflammasomes in intestinal inflammation and cancer

Grace Y Chen  1 , Gabriel Núñez
Affiliations
Review

Inflammasomes in intestinal inflammation and cancer

Grace Y Chen et al. Gastroenterology. 2011 Dec.

Abstract

Inflammasomes are multi-protein complexes that mediate activation of caspase-1, which promotes secretion of the proinflammatory cytokines interleukin-1β and interleukin-18 and pyroptosis, a form of phagocyte cell death induced by bacterial pathogens. Members of the Nod-like receptor family (including Nlrp1, Nlrp3, and Nlrc4), the DNA sensor Aim2, the adaptor apoptosis-associated speck-like protein (ASC), and pro-caspase-1 are important components of inflammasomes. Stimulation with specific microbial and endogenous molecules leads to inflammasome assembly and caspase-1 activation. Inflammasomes are believed to mediate host defense against microbial pathogens and tissue homeostasis within the intestine, and their dysregulation might contribute to inflammatory diseases and intestinal cancer. Improving our understanding of inflammasome signaling pathways could provide insights into the pathogenesis of many gastrointestinal disorders and the development of therapeutic targets and approaches to treat diseases such as inflammatory bowel diseases and gastrointestinal cancers.

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Figures

Figure 1
Figure 1. Inflammasome components and assembly
With the exception of Aim2 (not shown), all known inflammasomes consist of an NLR, which contain either a PYD domain or a CARD domain that can physically interact with the PYD or CARD domain of ASC and caspase-1, respectively. Both Nlrp1 and Nlrc4 contain a CARD domain that can directly independently of ASC; however, the addition of ASC in the inflammasome assembly can enhance its activity in the case of Nlrp1. The Nlrp3 inflammasome on the other hand may form different inflammasome complexes depending on the requirement for ASC. Oligomerization of ASC and the NLR results in a macromolecular complex consisting of multiple subunits that are capable of cleaving pro-caspase-1 to its active form, resulting in the cleavage of the pro-forms of IL-1β and IL-18 to their mature, biologically active forms. Activation of caspase-1 also leads to pyroptosis.
Figure 2
Figure 2. Activation of the Nlrp3 inflammasome requires 2 steps
A, Priming step: Based primarily on studies of Nlrp3, inflammasome activity requires first the production of pro-IL-1β and Nlrp3 through upregulation of NFκB by either activation of the TLRs or Nod1/2. Inflammatory cytokines such as TNFα or IL-1 can also induce NFκB. In addition, this first signal (i.e., cytokines, TLR or Nod1/2 activation) also results in the transcriptional upregulation of Nlrp3. B, Activation step: It remains unclear how Nlrp3 is activated by diverse signals. Three different mechanisms have been suggested: 1) Intracellular potassium depletion by the opening of a pore via ATP-dependent P2X7R activation or microbial pore-forming toxins, 2) lysosomal membrane damage and release of activated cathepsin B after endocytosis of sterile particulates such as silica, asbestos and cholesterol crystals, and 3) generation of ROS from the mitochondria as a consequence of cellular injury (although ROS may affect inflammasome priming only).
Figure 3
Figure 3. IL-18 is important for intestinal epithelial repair
Nlrp3-, ASC- and caspase-1-deficient mice have increased susceptibility to DSS-induced colitis. DSS causes direct epithelial injury resulting in increased permeability and translocation of bacteria into the breached mucosa leading to an inflammatory response that includes the recruitment of immune cells such as macrophages and neutrophils. The production of IL-18, such as by the Nlrp3-inflammasome, allows the epithelium to be fully restituted, limiting the extent of inflammation. The precise cellular source of IL-18 and how IL-18 promotes epithelial repair (e.g., whether it acts directly on the epithelial cell or indirectly through lamina propria cells) remain unclear.
Figure 4
Figure 4. Model of Nlrp6-mediated regulation of intestinal and microbial homeostasis
Nlrp6 maintains intestinal homeostasis by regulating the composition of the gut microbiome and the production of IL-18 (left). In the absence of Nlrp6 (right), there is dysbiosis resulting in the accumulation of colitogenic bacteria, upregulation of inflammatory mediators, such as CCL5, and subclinical inflammation. Upon additional epithelial damage by DSS, rampant inflammation ensues as a result of impaired epithelial repair from decreased IL-18 production..
Figure 5
Figure 5. The inflammasome protects against colitis-associated tumorigenesis through multiple mechanisms
Mice deficient in inflammasome activity have increased susceptibility to colitis-associated tumorigenesis. Specifically, Nlrp3, Nlrc4, and Nlrp6 all have been demonstrated to negatively regulate colitis-associated tumorigenesis (see text for details). Bone marrow chimera experiments suggest that Nlrp3 and Nlrp6 mediate tumor suppression within the hematopoietic compartment; however, mouse chimera experiments suggest that a non-hematopoietic compartment (epithelial or stromal cells) is important for Nlrc4-mediated tumor suppression. Although the mechanism still remains unclear, IL-18 may be an important factor in the protection against neoplasia by Nlrp3 and Nlrp6. Unlike Nlrp3 and Nlrp6, the absence of Nlrc4 signaling is not associated with increased inflammation. Instead, Nlrc4 appears to limit tumor development by regulating epithelial proliferation and apoptosis either in the intestinal epithelium or within the tumor itself.
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