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

• Published in: Frontiers in immunology 2022-07, Vol.13, p.840751
• Main Authors: Huijser, Erika, van Helden-Meeuwsen, Cornelia G, Grashof, Dwin G B, Tarn, Jessica R, Brkic, Zana, Huisman, Josje M A, Wahadat, M Javad, van de Werken, Harmen J G, Lopes, Ana P, van Roon, Joel A G, van Daele, Paul L A, Kamphuis, Sylvia, Ng, Wan-Fai, Bekkering, Siroon, Joosten, Leo A B, Dik, Willem A, Versnel, Marjan A
• Format: Article
• Language: English
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine; atherosclerosis; Atherosclerosis - metabolism; Glucose - metabolism; Humans; Immunology; Interferon Type I - metabolism; Interferon-beta - metabolism; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides - metabolism; monocytes; Phenotype; Poly I - metabolism; Sjogren's Syndrome; Sjögren’s syndrome; trained immunity; Tumor Necrosis Factor-alpha - metabolism; type I interferon (IFN)
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.840751

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 monocytic cell model and peripheral blood mononuclear cells (PBMCs) from pSS patients. The training stimuli heat killed , 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. Training with IFNβ induced elevated production of pro-atherogenic cytokines IL-6, TNFα and , differential cholesterol- and glycolysis-related gene expression, and increased glucose consumption and oxLDL uptake upon re-stimulation. Type I IFN production was increased in - 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 , 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. 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.