Interplay between Cellular and Molecular Mechanisms Underlying Inflammatory Bowel Diseases Development-A Focus on Ulcerative Colitis

Abstract

Inflammatory bowel diseases (IBD) are defined by the continuous inflammation of the gastrointestinal tract. During inflammation, the number of pathogens in the intestinal epithelium increases, leading to inflammasome assembly. Inflammasome activation is meant to protect the intestinal epithelial barrier from further damage by maintaining homeostasis. Although its purpose is to protect the cells, excessive nucleotide-binding oligomerization domain-like receptor and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly is responsible for the synthesis of a high number of pro-inflammatory cytokines. The activation of two crucial pathways, autophagy process, and unfolded protein response, is initiated for restoring homeostasis. Aberrant expression of miRNAs and lncRNAs also interfere with the pathogenic mechanisms of IBD, as these non-coding transcripts play key roles in regulation of biological processes, such as inflammation and immunity. This review thoroughly describes the cellular and molecular mechanism that trigger and perpetuate inflammation in ulcerative colitis (UC) patients.

Keywords: NLRP3; autophagy; inflammasome; inflammatory bowel diseases; miRNAs in IBD.

Figure 1

NLRP3 inflammasome activation can have protective and inflammatory effects in the intestinal epithelium. DAMPs and ATP molecules are recognized by TLRs on the IECs, which results in NLRP3 protein recruits adaptor protein ASC. This complex recruits pro-caspase 1, leading to inflammasome assembly and caspase-1 activation. Further on, activated caspase-1 promotes activation of pro-inflammatory cytokines IL-1β and IL-18. IL-18 is necessary for IECs proliferation, but excessive production of IL-18 leads to activation of immune cells and overproduction of pro-inflammatory cytokines, promoting inflammation.

Figure 2

Comparison between functional and defective process of autophagy. Extracellular signals, such as pathogens, activate adenosine monophosphate-activated protein kinase (AMPK), which initiates ULK1 complex and PI3K nucleation complex assembly. PI3K complex recruits ATG proteins at the isolation membrane for its expansion and closing, forming the autophagosome. Adaptor protein p62 binds to organelles and protein complexes and brings them in the autophagosome. The autophagosome fuses with the lysosome to form the autolysosome and degrade the organelles using lysosomal enzymes. Under stress conditions, loss of ATG7 and Atg16L1 increases production of IL-18 and IL-1β. Moreover, when p62 is affected and damaged mitochondria accumulates, NLRP3 inflammasome is activated and IL-1β production increases, leading to inflammation.

Figure 3

miRNAs correlation between UC and inflammatory bowel diseases (IBD), according to mirnet 1 network from miRNet. Up to this moment, there are 51 miRNAs known to be associated with UC pathology and 38 associated with IBD in general. This figure emphasizes the common miRNAs between UC and IBD in the case of inflammation, oxidative stress, immune response, and autophagy. Prolonged exposure to inflammation and oxidative stress could lead to tumorigenesis and colitis associated-colorectal cancer, based on the common miRNAs found in inflammation, immune response, oxidative stress, autophagy, and onco-miRNAs categories.