Prolonged exposure of mouse or human immune cells to unwanted microbial products –– such as lipopolysaccharide (LPS) –– can induce a form of innate immune memory that suppresses subsequent responses to unrelated pathogens. This is called “LPS tolerance”. Sepsis (presence of harmful bacteria and their toxins in tissues of an animal, typically through infection of a wound) is a dysregulated systemic immune response to disseminated infection that has a high mortality rate. In some patients, sepsis leads to a period of immunosuppression, known as “immunoparalysis,” which is characterized by diminished inflammatory cytokine output, increased secondary infection, and increased risk of organ failure and mortality.
Lipopolysaccharide (LPS) tolerance recapitulates several key features of sepsis-associated immunosuppression. LPS tolerance is an immunosuppressive form of innate immune memory that can be modeled in cultured cells by prolonged LPS treatment of bone-marrow-derived macrophages. As a result of this functional reprogramming, most LPS-induced genes are transcriptionally silenced (i.e. ‘tolerized’) and are not expressed during re-stimulation. Using this cell culture model, authors [see attached] identified microRNAs (miRNAs) with expression patterns that correlated with “tolerance”.
As these GEITP pages have often described, DNA-sequence changes reflect the inherited genotype. Heritable changes independent of DNA sequence represent epigenetic factors –– which include DNA methylation, RNA interference (RNAi), histone modifications, and chromatin remodeling. RNAi includes regulation of genes by miRNAs. Although various epigenetic changes have previously been observed in “tolerized” macrophages, the molecular basis of tolerance, immunoparalysis, and other forms of innate immune memory has remained unclear. Herein authors [see attached file] screened for tolerance-associated miRNAs and identified two specific miRNAs (miR-221 & miR-222) as regulators of functional reprogramming of macrophage genes during LPS tolerization.
Prolonged LPS stimulation in mice leads to increased expression of miR-221 and mir-222 –– both of which regulate the Smarca4 gene (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4). This increased expression causes transcriptional silencing of a subset of inflammatory genes that depend on chromatin-remodeling mediated by SWI/SNF (switch/sucrose non-fermentable) and STAT (signal transducer and activator of transcription). This, in turn, promotes LPS tolerance. In patients with sepsis, increased miR-221 and miR-222 expression is correlated with immunoparalysis and increased organ damage. This study shows that specific microRNAs can regulate macrophage tolerization, and this may serve as biomarkers of immunoparalysis and poor prognosis in patients who have developed sepsis.
In this story, therefore, “LPS treatment” or “sepsis” is the environmental signal, whereas genes identified as responding to this signal include the down-regulation (silencing) of a subset of inflammatory genes plus induction of two miRNAs, acting as epigenetic effects.
Nature 5 Jul 2o18; 559: 114–119