Korean J Gastroenterol.  2011 Dec;58(6):300-310. 10.4166/kjg.2011.58.6.300.

Inflammatory Bowel Diseases and Inflammasome

Affiliations
  • 1Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea. jungmogg@hanyang.ac.kr

Abstract

Inflammatory bowel disease (IBD), the most important entities being ulcerative colitis and Crohn's disease, are chronic, relapsing and remitting inflammatory conditions that result from chronic dysregulation of the mucosal immune system in the intestinal tract. Although the precise pathogenesis of IBD is still incompletely understood, increased levels of proinflammatory cytokines, including interleukin (IL)-1beta, IL-18 and tumor necrosis factor-alpha, are detected in active IBD and correlate with the severity of inflammation, indicating that these cytokines may play a key role in the development of IBD. Recently, the intracellular nucleotide-binding oligomerization domain-like receptor (NLR) family members, including NLRP1, NLRP3, NLRC4 and NLRP6, are emerging as important regulators of intestinal homeostasis. Together, one of those aforementioned molecules or the DNA sensor absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein containing 'a caspase recruitment domain (CARD)' (ASC) and caspase-1 form a large (>700 kDa) multi-protein complex called the inflammasome. Stimulation with specific microbial and endogenous molecules triggers inflammasome assembly and caspase-1 activation. Activated caspase-1 leads to the secretion of proinflammatory cytokines, including IL-1beta and IL-18, and the promotion of pyroptosis, a form of phagocyte cell death induced by bacterial pathogens, in an inflamed tissue. Therefore, inflammasomes are assumed to mediate host defense against microbial pathogens and gut homeostasis, so that their dysregulation might contribute to IBD pathogenesis. This review focuses on recent advances of the role of NLRP3 inflammasome signaling in IBD pathogenesis. Improving knowledge of the inflammasome could provide insights into potential therapeutic targets for patients with IBD.

Keyword

Inflammasomes; Inflammatory bowel diseases; Intestinal epithelial cells

MeSH Terms

CARD Signaling Adaptor Proteins/metabolism
Carrier Proteins/metabolism/physiology
Caspase 1/metabolism
Humans
Inflammasomes/*metabolism
Inflammatory Bowel Diseases/metabolism/*pathology
Interleukin-18/metabolism
Interleukin-1beta/metabolism
Signal Transduction

Figure

  • Fig. 1. Inflammasome signaling pathways. Nucleotide-binding oligomerization domain-like receptor (NLRP) within the cytosol of intestinal epithelial cells recognizes pathogen-associated molecular patterns (PAMPs) of the enteric microbiota and forms a multiprotein complex with apoptosis-associated speck-like protein containing ‘a caspase recruitment domain (CARD)' and caspase-1 called the ‘inflammasome.' NLRP3 is capable of sensing both PAMPs and endogenous damage-associated molecular patterns (DAMPs). The inflammasome plays a central role in the inflammatory process by activating caspase-1 and mediating production of proinflammatory cytokine interleukin (IL)-1β and IL-18. In addition, caspase-1 activation mediates pyroptosis, a specific form of early cell death induced by intracellular pathogens that promotes cellular lysis and the release of intracellular inflammatory contents to stimulate additional inflammatory signaling pathways.

  • Fig. 2. Hypothesis of nucleotide-binding oligomerization domain-like receptor (NLRP) 3 inflammasome-mediated protection against dextran sodium sulfate (DSS)-induced colitis and colitis-associated colon cancer (CAC) in mice model. DSS causes direct intestinal epithelial cell (IEC) injury, increasing permeability and translocation of bacteria into the mucosa, leading to inflammatory responses that include the recruitment of immune cells such as neutrophils and macrophages. In the stage of acute colitis, the production of interleukin (IL)-18 by the NLRP3 inflammasome may be involved in IEC repair. Chronic inflammation can lead to carcinogenesis via production of DNA-damaging oxygen radical species, proinflammatory mediators that promote cellular survival, and increases of epithelial proliferation and angiogenesis. In a murine model, the carcinogen azoxymethane is used to introduce genomic mutations by methylation. Although the mechanism still remains unclear, the downstream signaling of IL-18 and interferon-γ may play a role in inhibiting epithelial proliferation.


Cited by  1 articles

Roles of Enteric Microbial Composition and Metabolism in Health and Diseases
Jung Mogg Kim
Korean J Gastroenterol. 2013;62(4):191-205.    doi: 10.4166/kjg.2013.62.4.191.


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