Affiliation:
1. Systems Immunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
2. Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Abstract
Inflammatory bowel disease (IBD) is an idiopathic, chronic condition characterized by episodes of inflammation in the gastrointestinal tract. The nuclear factor κB (NF-κB) system describes a family of dimeric transcription factors. Canonical NF-κB signaling is stimulated by and enhances inflammation, whereas noncanonical NF-κB signaling contributes to immune organogenesis. Dysregulation of NF-κB factors drives various inflammatory pathologies, including IBD. Signals from many immune sensors activate NF-κB subunits in the intestine, which maintain an equilibrium between local microbiota and host responses. Genetic association studies of patients with IBD and preclinical mouse models confirm the importance of the NF-κB system in host defense in the gut. Other studies have investigated the roles of these factors in intestinal barrier function and in inflammatory gut pathologies associated with IBD. NF-κB signaling modulates innate and adaptive immune responses and the production of immunoregulatory proteins, anti-inflammatory cytokines, antimicrobial peptides, and other tolerogenic factors in the intestine. Furthermore, genetic studies have revealed critical cell type–specific roles for NF-κB proteins in intestinal immune homeostasis, inflammation, and restitution that contribute to the etiopathology of IBD-associated manifestations. Here, we summarize our knowledge of the roles of these NF-κB pathways, which are activated in different intestinal cell types by specific ligands, and their cross-talk, in fueling aberrant intestinal inflammation. We argue that an in-depth understanding of aberrant immune signaling mechanisms may hold the key to identifying predictive or prognostic biomarkers and developing better therapeutics against inflammatory gut pathologies.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Cell Biology,Molecular Biology,Biochemistry