Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of 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 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for in the control of the immune system is apparent from mouse studies, we know relatively little of the role of 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 human macrophages. Transcriptomic analysis reveals that activated macrophages are more pro-inflammatory than wild type controls and express elevated levels of , , and , but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as , and . THP1 macrophages recapitulate key observations in individuals with haploinsufficiency including decreased expression. These data supporting their utility as an model for understanding the role of in human monocytes and macrophages and indicate that of loss of function mutations in these cells is an important component in the associated pathology.