An epigenetic and transcriptomic signature of immune tolerance in human monocytes through multi-omics integration

Abstract

Background The plasticity of monocytes enables them to exert multiple roles during an immune response, including promoting immune tolerance. How monocytes alter their functions to convey immune tolerance in the context of lower respiratory tract infections in humans is not well understood. Here, we sought to identify epigenetic and transcriptomic features of cytokine production capacity in circulating monocytes during community-acquired pneumonia (CAP). Methods Circulating CD14+ monocytes were obtained from the blood of CAP patients included in a longitudinal, observational cohort study, on hospitalization (acute stage, n=75), and from the same patients after a 1-month follow-up (recovery stage, n=56). Age and sex-matched non-infectious participants were included as controls (n=41). Ex vivo cytokine production after lipopolysaccharide (LPS) exposure was assessed by multiplex assay. Transcriptomes of circulating monocytes were generated by RNA-sequencing, and DNA methylation levels in the same monocytes were measured by reduced representation bisulfite sequencing. Data were integrated by fitting projection-to-latent-structure models, and signatures derived by partial least squares discrimination. Results Monocytes captured during the acute stage exhibited impaired TNF, IL-1β, IL-6, and IL-10 production after ex vivo stimulation with LPS, relative to controls. IL-6 production was not resolved in recovery monocytes. Multivariate analysis of RNA-sequencing data identified 2938 significantly altered RNA transcripts in acute-stage monocytes (fold expression ≤−1.5 or ≥1.5; adjusted p ≤ 0.01), relative to controls. Comparing DNA methylation levels in circulating monocytes of CAP patients to controls revealed minimal differences, specifically in DNAse hypersensitive sites (HS) of acute-stage monocytes. Data integration identified a cholesterol biosynthesis gene signature and DNAse HS axis of IL-1β and IL-10 production (R2 =0.51). Conclusions Circulating monocytes obtained from CAP patients during the acute stage exhibited impaired cytokine production capacities, indicative of reprogramming to a state of immune tolerance, which was not fully resolved after 1 month. Our split-sample study showed that 51% of the immune tolerance phenotype can be explained, at least in part, by coordinated shifts in cholesterol biosynthesis gene expression and DNAse HS methylation levels. A multi-scale model identified an epigenetic and transcriptomic signature of immune tolerance in monocytes, with implications for future interventions in immunosuppression. Trial registration NCT number NCT02928367

Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial

“…Although non-referring to the entire study population, transcriptomic data indicated that genes involved in cholesterol biosynthesis were altered in clarithromycin-treated patients, relative to placebo, at study day 5. Other data also indicate the presence of an axis between cholesterol synthesis, antigen presentation and monocyte reprogramming toward a trained immunity phenotype [ 25 – 27 ]. Whether this axis is modulated by clarithromycin remains to be demonstrated.…”

Rectal microbiota are coupled with altered cytokine production capacity following community-acquired pneumonia hospitalization

“…To this end, CD14 + monocytes and polymorphonuclear leukocytes (PMNs) were obtained from patients with CAP at both timepoints and stimulated ex vivo for 24 h (monocytes) or 2 h (PMNs) with lipopolysaccharide (LPS) or heat-killed K. pneumoniae . Following stimulation, we measured a wide array of monocyte-derived cytokines and neutrophil-derived cytokines and degranulation products by multiplex assay ( STAR methods and previously reported by our group ( Brands et al., 2021 )). Of note, we observed no differences in leukocyte, lymphocyte, or neutrophil counts between clusters ( Table S2 ).…”

“…For transcriptional RNA profiling of monocytes, patients with previously diagnosed malignant hematological disease, or exposed to chemotherapy, systemic corticosteroids and/or other immunosuppressive drugs were excluded ( Brands et al., 2021 ).…”

“…Monocyte isolation and purity verification have been earlier described ( Brands et al., 2021 ). Heparinized blood was diluted (1:1) with phosphate-buffered saline (PBS).…”

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“…5 b). It has been shown that there was an association between cholesterol biosynthesis and impaired monocytes cytokine production in the context of human lower respiratory tract infections [ 74 ]. It is worth noting that all three cell types showed disturbance of the phospholipid metabolic process after METH treatment (Fig.…”