Defining the role of nuclear factor NF-κB p105 subunit in human macrophage by transcriptomic analysis of NFKB1 knockout THP-1 cells

Somma, D., Kok, F. O., Kerrigan, D., Wells, C. A. and Carmody, R. J. (2021) Defining the role of nuclear factor NF-κB p105 subunit in human macrophage by transcriptomic analysis of NFKB1 knockout THP-1 cells. Frontiers in Immunology, 12, 669906. (doi: 10.3389/fimmu.2021.669906) (PMCID:PMC8548695)

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Abstract

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 NFKB1 gene as the most common monogenic cause of common variable immunodeficiencies in Europeans. NFKB1 encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit. NFKB1 is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for NFKB1 in the control of the immune system is apparent from Nfkb1-/- mouse studies, we know relatively little of the role of NFKB1 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 NFKB1-/- human macrophages. Transcriptomic analysis reveals that activated NFKB1-/- macrophages are more pro-inflammatory than wild type controls and express elevated levels of TNF, IL6, and IL1B, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as CD70, CD83 and CD209. NFKB1-/- THP1 macrophages recapitulate key observations in individuals with NFKB1 haploinsufficiency including decreased IL10 expression. These data supporting their utility as an in vitro model for understanding the role of NFKB1 in human monocytes and macrophages and indicate that of loss of function NFKB1 mutations in these cells is an important component in the associated pathology.

Item Type:Articles
Additional Information:This work was supported by the Medical Research Council (MR/M010694/1) and Biotechnology and Biological Sciences Research Council (BB/M003671/1 and BB/T007427/1).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Wells, Dr Christine and Kok, Dr Fatma and Kerrigan, Mr David and Carmody, Dr Ruaidhri and Somma, Domenico
Authors: Somma, D., Kok, F. O., Kerrigan, D., Wells, C. A., and Carmody, R. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Immunology
Publisher:Frontiers Media
ISSN:1664-3224
ISSN (Online):1664-3224
Copyright Holders:Copyright © 2021 Somma, Kok, Kerrigan, Wells and Carmody
First Published:First published in Frontiers in Immunology 12:669906
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190848Investigating NF-kB p50 phosphorylation and the regulation of transcriptionRuaidhri CarmodyMedical Research Council (MRC)MR/M010694/1III - Immunology
190815Dissecting the function of Bcl-3 in NF-kappaB signaling in B cellsRuaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/M003671/1III - Immunology
306394A structure-function analysis of USP7 and NF-kB interaction.Ruaidhri CarmodyBiotechnology and Biological Sciences Research Council (BBSRC)BB/T007427/1III - Immunology