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Trained Immunity in Primary Sjögren’s Syndrome: Linking Type I Interferons to a Pro-Atherogenic Phenotype

Lookup NU author(s): Dr Jessica Tarn, Professor Fai NgORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

Copyright © 2022 Huijser, van Helden-Meeuwsen, Grashof, Tarn, Brkic, Huisman, Wahadat, van de Werken, Lopes, van Roon, van Daele, Kamphuis, Ng, Bekkering, Joosten, Dik and Versnel.Background: Trained immunity – or innate immune memory – can be described as the long-term reprogramming of innate immune cells towards a hyperresponsive state which involves intracellular metabolic changes. Trained immunity has been linked to atherosclerosis. A subgroup of patients with primary Sjögren’s syndrome (pSS) exhibits systemic type I interferon (IFN) pathway activation, indicating innate immune hyperactivation. Here, we studied the link between type I IFNs and trained immunity in an in vitro monocytic cell model and peripheral blood mononuclear cells (PBMCs) from pSS patients. Methods: The training stimuli heat killed Candida albicans, muramyl dipeptide, IFNβ, and patient serum were added to THP-1 cells for 24 hours, after which the cells were washed, rested for 48 hours and subsequently re-stimulated with LPS, Pam3Cys, poly I:C, IFNβ or oxLDL for 4-24 hours. PBMCs from pSS patients and healthy controls were stimulated with LPS, Pam3Cys, poly I:C or IFNβ for 0.5-24 hours. Results: Training with IFNβ induced elevated production of pro-atherogenic cytokines IL-6, TNFα and CCL2, differential cholesterol- and glycolysis-related gene expression, and increased glucose consumption and oxLDL uptake upon re-stimulation. Type I IFN production was increased in Candida albicans- and IFNβ-trained cells after LPS re-stimulation, but was reduced after poly I:C re-stimulation. Training with muramyl dipeptide and IFNβ, but not Candida albicans, affected the IFN-stimulated gene expression response to IFNβ re-stimulation. PBMCs from pSS patients consumed more glucose compared with healthy control PBMCs and tended to produce more TNFα and type I IFNs upon LPS stimulation, but less type I IFNs upon poly I:C stimulation. Conclusions: Type I IFN is a trainer inducing a trained immunity phenotype with pro-atherogenic properties in monocytes. Conversely, trained immunity also affects the production of type I IFNs and transcriptional response to type I IFN receptor re-stimulation. The phenotype of pSS PBMCs is consistent with trained immunity. This connection between type I IFN, trained immunity and cholesterol metabolism may have important implications for pSS and the pathogenesis of (subclinical) atherosclerosis in these patients.

Publication metadata

Author(s): Huijser E, van Helden-Meeuwsen CG, Grashof DGB, Tarn JR, Brkic Z, Huisman JMA, Wahadat MJ, van de Werken HJG, Lopes AP, van Roon JAG, van Daele PLA, Kamphuis S, Ng W-F, Bekkering S, Joosten LAB, Dik WA, Versnel MA

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2022

Volume: 13

Online publication date: 04/07/2022

Acceptance date: 30/05/2022

Date deposited: 08/08/2022

ISSN (electronic): 1664-3224

Publisher: Frontiers Media S.A.

URL: https://doi.org/10.3389/fimmu.2022.840751

DOI: 10.3389/fimmu.2022.840751

Data Access Statement: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE173670.

PubMed id: 35860283

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