Induction of innate immune memory via microRNA targeting of chromatin remodelling factors

John J. Seeley, Rebecca G. Baker, Ghait Mohamed, Tony Bruns, Matthew S. Hayden, Sachin D. Deshmukh, Daniel E. Freedberg and Sankar Ghosh ()
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John J. Seeley: College of Physicians & Surgeons, Columbia University
Rebecca G. Baker: College of Physicians & Surgeons, Columbia University
Ghait Mohamed: The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital
Tony Bruns: The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital
Matthew S. Hayden: College of Physicians & Surgeons, Columbia University
Sachin D. Deshmukh: The Integrated Research and Treatment Center for Sepsis Control and Care, Jena University Hospital
Daniel E. Freedberg: Division of Digestive & Liver Disease, College of Physicians & Surgeons, Columbia University
Sankar Ghosh: College of Physicians & Surgeons, Columbia University

Nature, 2018, vol. 559, issue 7712, 114-119

Abstract: Abstract Prolonged exposure to microbial products such as lipopolysaccharide can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens, known as lipopolysaccharide tolerance. Sepsis is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis results in a period of immunosuppression (known as ‘immunoparalysis’)1 characterized by reduced inflammatory cytokine output2, increased secondary infection3 and an increased risk of organ failure and mortality4. Lipopolysaccharide tolerance recapitulates several key features of sepsis-associated immunosuppression5. Although various epigenetic changes have previously been observed in tolerized macrophages6–8, the molecular basis of tolerance, immunoparalysis and other forms of innate immune memory has remained unclear. Here we perform a screen for tolerance-associated microRNAs and identify miR-221 and miR-222 as regulators of the functional reprogramming of macrophages during lipopolysaccharide tolerization. Prolonged stimulation with lipopolysaccharide in mice leads to increased expression of miR-221 and mir-222, both of which regulate brahma-related gene 1 (Brg1, also known as Smarca4). This increased expression causes the transcriptional silencing of a subset of inflammatory genes that depend on chromatin remodelling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription), which in turn promotes tolerance. In patients with sepsis, increased expression of miR-221 and miR-222 correlates with immunoparalysis and increased organ damage. Our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in patients with sepsis.

Date: 2018
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DOI: 10.1038/s41586-018-0253-5

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