Journal Article

Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma

Einhaus, Jakob, Ghaemi, Sajjad, Tsai, Amy S, Rumer, Kristen K, Aghaeepour, Nima, Gaudilliere, Brice, Verdonk, Franck, Fallahzadeh, Ramin, Culos, Anthony, Ganio, Edward A, Kehlet, Henrik, Stelzer, Ina A, Choisy, Benjamin, Angst, Martin S, Stanley, Natalie, Lindberg-Larsen, Viktoria, Gaudilliere, Dyani, Tsai, Eileen

2020

Overview

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC = 0.92, p-value = 3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs’ effects on clinical outcomes likely dependent on functional adaptive immune responses.

• Publisher: Nature Research,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 631/1647/48 / 631/250/256/2516 / 631/250/516 / 692/699/578 / Acute Disease / acute inflammation / Adaptive immunity / Adaptive Immunity - drug effects / Adaptive systems / Aged / Arthroplasty, Replacement, Hip - adverse effects / bioinformatics / Case-Control Studies / Clustering / Cyclic AMP response element-binding protein / Double-Blind Method / Fatigue - drug therapy / Female / Flow cytometry / Glucocorticoids / Glucocorticoids - pharmacology / Humanities and Social Sciences / Humans / Immune response / Immune system / Immunomodulation / Inflammation / Innate immunity / Male / Methylprednisolone / Methylprednisolone - pharmacology / Methylprednisolone - therapeutic use / multidisciplinary / NF-KappaB Inhibitor alpha - metabolism / Pain / Pain - drug therapy / Patients / Phenotype / Phosphorylation / Recovery of function / Science / Science (multidisciplinary) / Sepsis / signal transduction / Signaling / Stat3 protein / STAT3 Transcription Factor - metabolism / Surgery / System dynamics / Trauma / Treatment Outcome / Wounds and Injuries - etiology / Wounds and Injuries - immunology