Dysregulated inflammasome activity in intestinal inflammation – Insights from patients with very early onset IBD

Abstract

Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.

A randomized, double‐blind phase 1b study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of the NLRP3 inhibitor selnoflast in patients with moderate to severe active ulcerative colitis

“…15 Aberrant activation of the NLRP3 inflammasome has been implicated in a broad spectrum of inflammatory disorders including atherosclerosis, Alzheimer's disease, gastrointestinal cancers, and UC. 15,16 NLRP3 and IL-1β are upregulated in active UC, 17 and genomic studies have shown that polymorphisms in NLRP3-related genes may affect individual susceptibility to IBD. 14 Finally, inhibition of IL-1β and IL-18 downstream of NLRP3 inflammasome signaling ameliorates gut inflammation in several animal models of colitis.…”

“…The NLRP3 inflammasome is activated upon exposure to diverse signals, such as pathogen‐associated molecular patterns (PAMPs), danger‐associated molecular patterns (DAMPs), dead cells, and external irritants 15 . Aberrant activation of the NLRP3 inflammasome has been implicated in a broad spectrum of inflammatory disorders including atherosclerosis, Alzheimer's disease, gastrointestinal cancers, and UC 15,16 . NLRP3 and IL‐1β are upregulated in active UC, 17 and genomic studies have shown that polymorphisms in NLRP3‐related genes may affect individual susceptibility to IBD 14 .…”

Novel Biomarkers for Inflammatory Bowel Disease and Colorectal Cancer: An Interplay between Metabolic Dysregulation and Excessive Inflammation

“…It can be disturbed/damaged during the pathogenesis of inflammatory disorders such as IBD [ 12 , 13 , 14 ]. Active IBD is characterized by pronounced infiltration of the lamina propria with innate immunity cells (macrophages, dendritic, and natural killer cells), as well as a later phase of infiltration of adaptive immune cells (B and T lymphocytes) stimulating the production of T regulatory cells (Treg), Th1, Th2, and Th17 cytokines [ 14 , 15 , 16 ]. Following inflammatory directed injury, the intestinal epithelial cell layer integrity needs to be re-established in a timely manner by the process of epithelial restitution (or resealing of the epithelial barrier), wound healing, and/or increased epithelial proliferation [ 17 , 18 , 19 ].…”

The Interface between Inflammatory Bowel Disease, Neuroinflammation, and Neurological Disorders

“…Although the mechanistic underpinnings leading to the development and pathophysiology of IBD are not fully delineated, they correlate with abnormalities in both the adaptive and innate immune systems. 11 Furthermore, it is thought that an overactive mucosal immune response against gut microbiota in a subset of genetically susceptible individuals is responsible for the disease. 12 Gut microbiota are crucial components necessary for immune system development and maturation.…”