Abstract
The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory response. In the first part of this review, we discuss the NF-κB inducers, signaling pathways, and regulators involved in immune homeostasis as well as detail the importance of post-translational regulation by ubiquitination in NF-κB function. We also indicate the stages of central and peripheral tolerance where NF-κB plays a fundamental role. With respect to central tolerance, we detail how NF-κB regulates medullary thymic epithelial cell (mTEC) development, homeostasis, and function. Moreover, we elaborate on its role in the migration of double-positive (DP) thymocytes from the thymic cortex to the medulla. With respect to peripheral tolerance, we outline how NF-κB contributes to the inactivation and destruction of autoreactive T and B lymphocytes as well as the differentiation of CD4+-T cell subsets that are implicated in immune tolerance. In the latter half of the review, we describe the contribution of NF-κB to the pathogenesis of autoimmunity and autoinflammation. The recent discovery of mutations involving components of the pathway has both deepened our understanding of autoimmune disease and informed new therapeutic approaches to treat these illnesses.
Highlights
Reviewed by: Ruaidhri Carmody, University of Glasgow, United Kingdom Patrick Leung, University of California, Davis, United States
The study of patients presenting with Primary immunodeficiencies (PIDs) has revealed a wide variety of genes responsible for autoimmunity and autoinflammation linked to the NF-kB signaling pathway (Table 1)
It actively participates in central immune tolerance and is a key player in peripheral immune tolerance in secondary hematopoietic organs and circulating blood
Summary
Much of the research over the past few decades has centered on the immune system’s involvement in a constant balancing act. The second is to control mature self-reactive T-cells [93] These mechanisms include Fas-mediated apoptosis, causing clonal deletion of T-cells as well as the suppressive function of regulatory T-cells (Tregs) (Figure 5B). Mice lacking canonical NF-kB pathway signaling components produce fewer Treg cells These components include the lymphocyte-specific TAK1/IKKactivating factors CARMA1, IKK, BCL10, and TAK1 (Figure 5B). A significant decrease in the development of Treg has been observed in mice that have a deletion in the IKK negative regulator CYLD or express constitutive IKKb activity [108]. The in vivo function of Tregs is compromised by the ablation of the conjugating enzyme that is specific for the K63 ubiquitin chain This leads to the development of autoimmunity as well as impaired T-cell homeostasis [110]. Steady-state accumulation of DCs in draining lymph nodes requires NF-kB signaling [115]
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