Nod-like receptors (NLRs) are intracellular pattern recognition receptors that are responsible for detecting invading pathogens and activating the innate immune response. Upon recognition of microbial components, some NLRs form cytoplasmic, multiprotein complexes known as inflammasomes that serve as platforms for the recruitment, cleavage, and activation of inflammatory caspases. Inflammasome activation of Caspase-1 is essential for the maturation and secretion of IL-1 beta and IL-18, two closely related IL-1 family cytokines that function as key mediators of the host immune response.
Several reports have established a link between defects in the inflammasome pathway and pathological conditions. The autoinflammatory disorders, Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory Syndrome (FACS), and Neonatal-Onset Multisystem Inflammatory Disease (NOMID), are associated with mutations in NLRP3 that lead to constitutive activation of the NLRP3 inflammasome. In contrast, single nucleotide polymorphisms that reduce NLRP3 expression have recently been shown to be associated with an increased susceptibility to inflammatory bowel disease (IBD).1 While autoinflammatory disorders seem to be primarily caused by elevated levels of active IL-1 beta, IL-18 is thought to be the critical effector molecule in intestinal disorders. This is based on the paradoxical findings that both a lack of IL-18 and IL-18 overexpression in experimental mouse models are associated with exacerbated intestinal inflammation in response to induced colonic epithelial damage.2, 3, 4, 5 In addition, IL-18 in humans is upregulated in colon tissue from patients with Crohn's disease.6 Together, these observations imply that IL-18 may have both protective and detrimental effects in regulating mucosal immunity.
Two recent studies in mice provide further evidence that the Nlrp3 inflammasome, Caspase-1, and IL-18 are required for protection against colitis.7, 8 This was revealed by investigating the phenotypes of mice lacking different components of the Nlrp3 inflammasome following a five day treatment with dextran sodium sulfate (DSS), a polysaccharide that is toxic to the colonic epithelium.7, 8 Treatment of Caspase-1-/- or Nlrp3-/- mice with DSS led to intestinal bleeding, shortening of the colon, a significant increase in weight loss and lower survival rates compared to DSS-treated wild-type mice. Following DSS treatment, Caspase-1-/- and Nlrp3-/- mice also showed signs of increased bacterial invasion in the mesenteric lymph nodes, colon, and spleen or liver. The high levels of bacterial dissemination suggest that the inflammasome pathway is required for reestablishing the integrity of the epithelial layer following intestinal tissue damage.8
||Nlrp3-mediated IL-18 Secretion Can Have Protective or Destructive Effects in the Intestine. Current data is consistent with a model that suggests that the Nlrp3 inflammasome can have either protective or deleterious effects in the intestine depending on the cell type in which it is activated. In response to acute colitis induced by dextran sodium sulfate (DSS), inflammasome activation in intestinal epithelial cells (IECs) and the subsequent secretion of IL-18 are necessary for IEC proliferation and tissue regeneration. Inflammasome activity in IECs limits mucosal damage and prevents stimulation of immune cells in the lamina propria. In contrast, chronic DSS exposure results in inflammasome activation in intestinal immune cells, potentially leading to the overproduction of inflammatory cytokines and subsequent tissue destruction.
To determine whether intestinal tissue repair was dependent on IL-1 beta or IL-18, the concentration of each cytokine in the serum of DSS-treated wild-type mice was examined.7, 8 While the levels of IL-1 beta increased modestly in response to DSS, IL-18 levels increased dramatically, both in the serum and in the colon itself. IL-18 was produced primarily by nonhematopoietic cells, rather than macrophages or dendritic cells present in the lamina propria.7 To determine the functional significance of increased IL-18 production, recombinant IL-18 was injected into Caspase-1-/- mice, zero to two days following DSS treatment.7 The addition of exogenous IL-18 allowed DSS-treated, Caspase-1-deficient mice to survive and maintain a stable body weight, demonstrating that IL-18 is the key factor required for protection against DSS-induced colitis. These results suggest that reduced IL-18 production by intestinal epithelial cells following acute activation may compromise the mucosal barrier and increase susceptibility to intestinal inflammatory disorders.
Chronic inflammation associated with IBD increases the risk of developing colorectal cancer.9 Significantly, a connection between the inflammasome pathway and colitis-associated colorectal cancer has also recently been identified.7, 10 Consistent with the inflammasome playing a protective role, Allen et al. demonstrated that mice lacking Caspase-1, ASC, or Nlrp3 were more susceptible than wild-type mice to inflammation-associated colorectal tumor development induced by the procarcinogen azoxymethane and recurring cycles of DSS administration.10 In contrast, mice lacking Caspase-12, a negative regulator of Caspase-1, also displayed enhanced tumorigenesis following a similar treatment regimen.7 While together these studies clearly establish a connection between the inflammasome and colitis-associated tumorigenesis, further research is necessary to clarify the regulatory mechanisms by which the inflammasome pathway can both inhibit and promote intestinal inflammation. Understanding these mechanisms may have therapeutic implications for IBD and colitis-associated colorectal cancer.
- Villani, A-C. et al. (2009) Nat. Genet. 41:71.
- Ishikura, T. et al. (2003) J. Gastroenterol. Hepatol. 18:960.
- Sivakumar, P.V. et al. (2002) Gut 50:812.
- Takagi, H. et al. (2003) Scand. J. Gasteroenterol. 38:837.
- Coruh, B. et al. (2001) Gasteroenterology 120:A-122.
- Pizarro, T.T. et al. (1999) J. Immunol. 162:6829.
- Dupaul-Chicoine, J. (2010) Immunity 32:367.
- Zaki, M. H. et al. (2010) Immunity 32:379.
- Clevers, H. (2004) Cell 118:671.
- Allen, I.C. et al. (2010) J. Exp. Med. 207:1045.
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