Nuclear factor NF-kappa-B p105 subunit
DNA-binding transcription activator activity, RNA polymerase II-specific
Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of <i>NFKB1</i> Knockout THP1 Cells.
Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the <i>NFKB1</i> gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. <i>NFKB1</i> encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. <i>NFKB1</i> is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for <i>NFKB1</i> in the control of the immune system is apparent from <i>Nfkb1<sup>-/-</sup></i> mouse studies, we know relatively little of the role of <i>NFKB1</i> in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of <i>NFKB1<sup>-/-</sup></i> human macrophages. Transcriptomic analysis reveals that activated <i>NFKB1<sup>-/-</sup></i> macrophages are more pro-inflammatory than wild type controls and express elevated levels of <i>TNF</i>, <i>IL6</i>, and <i>IL1B</i>, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as <i>CD70</i>, <i>CD83</i> and <i>CD209</i>. <i>NFKB1</i><sup>-/-</sup> THP1 macrophages recapitulate key observations in individuals with <i>NFKB1</i> haploinsufficiency including decreased <i>IL10</i> expression. These data supporting their utility as an <i>in vitro</i> model for understanding the role of <i>NFKB1</i> in human monocytes and macrophages and indicate that of loss of function <i>NFKB1</i> mutations in these cells is an important component in the associated pathology.