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

Prolonged exposure to microbial products, e.g. lipopolysaccharide (LPS), can induce a form of innate immune memory that blunts subsequent responses to unrelated pathogens (“LPS tolerance”). Sepsis, which continues to have a high mortality rate, is a dysregulated, systemic immune response to disseminated infection. In some patients, this results in a period of immunosuppression (“immunoparalysis”)(1) with reduced inflammatory cytokine output(2), increased secondary infection(3), and increased risk of organ failure and mortality(4). LPS tolerance recapitulates several key features of sepsis-associated immunosuppression(5). Although various epigenetic changes have been observed in tolerized macrophages(6–8), the molecular basis for tolerance, immunoparalysis, and other forms of innate immune memory has remained unclear. Here, we performed a screen for tolerance-associated microRNAs (miRNAs) and identified miR-221/222 as regulators of the functional reprogramming of macrophages during LPS tolerization. Prolonged stimulation with LPS in mice leads to Increased expression of miR-221/222, which regulates brahma-related gene 1 (Brg1) causing transcriptional silencing of a subset of inflammatory genes that depend on SWI/SNF- (SWItch/Sucrose Non-Fermentable) and STAT- (signal transducer and activator of transcription) mediated chromatin remodeling, and promotes tolerance. In sepsis patients, increased miR-221/222 expression correlates with immunoparalysis and increased organ damage. Hence our results show that specific microRNAs can regulate macrophage tolerization and may serve as biomarkers of immunoparalysis and poor prognosis in sepsis patients.