Macrophage-Specific NF-κB Activation Dynamics Can Segregate Inflammatory Bowel Disease Patients

Papoutsopoulou, Stamatia ORCID: 0000-0001-6665-8508, Burkitt, Michael D ORCID: 0000-0002-5055-6408, Bergey, Francois, England, Hazel, Hough, Rachael, Schmidt, Lorraine, Spiller, David G, White, Michael HR, Paszek, Pawel, Jackson, Dean A
et al (show 6 more authors) (2019) Macrophage-Specific NF-κB Activation Dynamics Can Segregate Inflammatory Bowel Disease Patients. FRONTIERS IN IMMUNOLOGY, 10. 2168-.

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The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-κB transcription factor is a highly regulated, dynamic event in IBD pathogenesis. Using a lentivirus approach, NF-κB-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-κB-regulated luciferase response. The ulcerative colitis (UC) samples appeared only in the hypo-responsive Cluster 1, and in Cluster 2. Conversely, Crohn's disease (CD) patients appeared in all Clusters with their percentage being higher in the hyper-responsive Cluster 3. A positive correlation was seen between NF-κB-induced luciferase activity and the concentrations of cytokines released into medium from stimulated macrophages, but not with serum or biopsy cytokine levels. Confocal imaging of lentivirally-expressed p65 activation revealed that a higher proportion of macrophages from CD patients responded to endotoxin lipid A compared to controls. In contrast, cells from UC patients exhibited a shorter duration of NF-κB p65 subunit nuclear localization compared to healthy controls, and CD donors. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between CD patients who smoked and hyper-activation of p65. These <i>in vitro</i> dynamic assays of NF-κB activation in blood-derived macrophages have the potential to segregate IBD patients into groups with different phenotypes and may therefore help determine response to therapy.

Item Type: Article
Uncontrolled Keywords: inflammatory bowel disease, NF-kappa B, macrophages, cytokines, Crohn's disease, ulcerative colitis
Depositing User: Symplectic Admin
Date Deposited: 24 Sep 2019 10:39
Last Modified: 16 Oct 2023 18:01
DOI: 10.3389/fimmu.2019.02168
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