Dysregulation of intestinal epithelial cell RIPK pathways promotes chronic inflammation in the IBD gut

Abstract

Crohn's disease (CD) and ulcerative colitis (UC) are common intestinal bowel diseases (IBD) characterized by intestinal epithelial injury including extensive epithelial cell death, mucosal erosion, ulceration, and crypt abscess formation. Several factors including activated signaling pathways, microbial dysbiosis, and immune deregulation contribute to disease progression. Although most research efforts to date have focused on immune cells, it is becoming increasingly clear that intestinal epithelial cells (IEC) are important players in IBD pathogenesis. Aberrant or exacerbated responses to how IEC sense IBD-associated microbes, respond to TNF stimulation, and regenerate and heal the injured mucosa are critical to the integrity of the intestinal barrier. The role of several genes and pathways in which single nucleotide polymorphisms (SNP) showed strong association with IBD has recently been studied in the context of IEC. In patients with IBD, it has been shown that the expression of specific dysregulated genes in IECs plays an important role in TNF-induced cell death and microbial sensing. Among them, the NF-κB pathway and its target gene TNFAIP3 promote TNF-induced and receptor interacting protein kinase (RIPK1)-dependent intestinal epithelial cell death. On the other hand, RIPK2 functions as a key signaling protein in host defense responses induced by activation of the cytosolic microbial sensors nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1 and NOD2). The RIPK2-mediated signaling pathway leads to the activation of NF-κB and MAP kinases that induce autophagy following infection. This article will review these dysregulated RIPK pathways in IEC and their role in promoting chronic inflammation. It will also highlight future research directions and therapeutic approaches involving RIPKs in IBD. Inflammatory bowel disease (IBD) is an inflammatory process with a chronic relapsing course that is characterized pathologically by intestinal inflammation and epithelial injury that affects the different gastrointestinal (GI) linings (1). IBD includes different inflammatory pathologies of the gastrointestinal track. The more prevalent IBD pathologies are Crohn's Disease (CD) and Ulcerative Colitis (UC) (1). Pathogenesis of IBD is multifactorial, involving genetic predisposition, disturbance of the commensal microbiota, epithelial barrier defects, dysregulated immune responses, and environmental factors (2). The gastrointestinal tract (in particular, the terminal ileum and colon) also contains a massive bacterial load that has the potential to initiate an acute inflammatory intestinal response if the mucosal barrier is breached and bacteria gain access to the lamina propria, as occurs in IBD (2). The receptor interacting protein kinase (RIPK) proteins are key molecules for the maintainance of a healthy intestinal barrier (3). The RIPK family contains seven members that share a homologous serine-threonine kinase domain but has different functional domains (4). RIPK1 contains a death-domain in the C-terminal portion that allows its recruitment to different signaling complexes. RIPK2 is characterized by its caspase activation and recruitment domain (CARD). RIPK3, like RIPK1, has a RIP homotypic interaction motif (RHIM), which is necessary for RIPK1 and RIPK3 dimerization. RIPK4 (or DIK or PKK) and RIPK5 (or SgK288) contain ankyrin repeats in the C-terminal tail. Finally, RIPK6 (or LRRK1) and RIPK7 (LRRK2) have leucine-rich repeats (LRR) that could play a role in the recognition of inflammatory-associated molecular patterns. In this review, we will focus on the epithelial barrier and how an aberrant response to TNF stimulation, exarcebated, IBD-associated microbial sensing, and abnormal regeneration and healing of the injured mucosa by dysregulated RIPK pathways in IEC can critically affect the health of the intestinal barrier.