The role and function of IκKα/β in monocyte impairment

Galbraith, N. J. et al. (2020) The role and function of IκKα/β in monocyte impairment. Scientific Reports, 10, 12222. (doi: 10.1038/s41598-020-68018-x) (PMID:32699255) (PMCID:PMC7376008)

Abstract

Following major trauma, sepsis or surgery, some patients exhibit an impaired monocyte inflammatory response that is characterized by a decreased response to a subsequent bacterial challenge. To investigate this poorly understood phenomenon, we adopted an in-vitro model of endotoxin tolerance utilising primary human CD14 + monocytes to focus on the effect of impairment on IκKα/β, a critical part of the NFκB pathway. Impaired monocytes had decreased IκKα mRNA and protein expression and decreased phosphorylation of the IκKα/β complex. The impaired monocyte secretome demonstrated a distinct cytokine/chemokine footprint from the naïve monocyte, and that TNF-α was the most sensitive cytokine or chemokine in this setting of impairment. Inhibition of IκKα/β with a novel selective inhibitor reproduced the impaired monocyte phenotype with decreased production of TNF-α, IL-6, IL-12p70, IL-10, GM-CSF, VEGF, MIP-1β, TNF-β, IFN-α2 and IL-7 in response to an LPS challenge. Surgical patients with infection also exhibited an impaired monocyte phenotype and had decreased SITPEC, TAK1 and MEKK gene expression, which are important for IκKα/β activation. Our results emphasize that impaired monocyte function is, at least in part, related to dysregulated IκKα/β activation, and that IκKα/β is likely involved in mounting a sufficient monocyte inflammatory response. Future studies may wish to focus on adjuvant therapies that augment IκKα/β function to restore monocyte function in this clinically important problem.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Galbraith, Dr Norman

Creator Roles

Galbraith, N.: Data curation, Formal analysis, Writing – original draft

• Authors: Galbraith, N. J., Gardner, S. A., Walker, S. P., Trainor, P., Carter, J. V., Bishop, C., Sarojini, H., O’Brien, S. J., Bhatnagar, A., Polk, H. C., and Galandiuk, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Scientific Reports 10:12222
• Publisher Policy: Reproduced under a Creative Commons licence